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Bonadeo N, Chimento A, Mejía ME, Dallard BE, Sorianello E, Becu-Villalobos D, Lacau-Mengido I, Cristina C. NOTCH and IGF1 signaling systems are involved in the effects exerted by anthelminthic treatment of heifers on the bovine mammary gland. Vet Parasitol 2025; 334:110390. [PMID: 39798247 DOI: 10.1016/j.vetpar.2025.110390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 01/03/2025] [Accepted: 01/05/2025] [Indexed: 01/15/2025]
Abstract
Dairy heifers with gastrointestinal nematodes have reduced growth rates, and delayed age at puberty and milk production onset related to late mammary gland development. IGF1 and Notch signaling systems are important in this process, and an altered profile of serum IGF1 has been associated with the detrimental effect of the nematodes on parenchymal development. In this context, we aimed to study the molecular mechanisms involved in bovine mammary gland development around pre and postpuberty, focusing on proliferative and angiogenic processes that involve the Notch and IGF1 pathways. We used mammary tissue samples from pre and pubertal heifers, treated or untreated with anthelmintics, and MAC-T bovine mammary epithelial cells in vitro. Anthelminthic treatment effectively lowered EPG in feces. Mammary glands from treated heifers had increased proliferation rate (measured by PCNA) and angiogenic marker expression (VEGF and CD34), as well as increased αSMA area compared to age-matched control parasitized heifers. These changes were preceded by increased expression of Notch targets at 20 wk of age (HES1, HEY2, and HEY1), indicating a possible interaction. Similarly, IGF1R expression was increased at 30 weeks of age. To study the crosstalk between systems, bovine MAC-T cells were treated with DAPT (50 μM) to inhibit Notch signaling. DAPT decreased the proliferation of cells as evidenced by a decrease in PCNA, pERK, CYCYLIN D1; and the wound healing capacity of HMEC cells was impaired in the presence of the supernatants of DAPT-treated cells. Furthermore, DAPT decreased IGF1 and increased IGF1R mRNA levels in MAC-T cells. On the other hand, cells treated with 10 ng/mL IGF1 Increased their proliferation (MTS assay), and induced a strong tendency to increase Notch target genes (HEY1, and HES1). Furthermore, IGF1 treatment tampered the decrease in the proliferation rate induced by DAPT. Finally, a positive correlation between the IGF1R and Notch target genes (HEY1, and HES1) further suggested a relation between these two signaling systems in the bovine mammary gland. In conclusion, pubertal delay related to parasitosis is counteracted by anthelminthic treatments, which increase serum IGF1, mammary cell proliferation, and angiogenesis. We postulate the Notch pathway, mainly through the HEY1 target gene, which is modulated by the IGF1 system, may regulate both proliferative and angiogenic processes favoring normal development of the bovine mammary gland during puberty. In addition, we demonstrate that the interaction between the Notch and the IGF1 pathways may affect cell proliferation.
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Affiliation(s)
- Nadia Bonadeo
- Centro de Investigaciones Básicas y Aplicadas, Universidad Nacional del Noroeste de la Provincia de Buenos Aires, Junín, Buenos Aires 6000, Argentina; Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires, CITNOBA, UNNOBA - UNSAdA - CONICET, Monteagudo 2772, Pergamino, Buenos Aires 2700, Argentina
| | - Agustina Chimento
- Centro de Investigaciones Básicas y Aplicadas, Universidad Nacional del Noroeste de la Provincia de Buenos Aires, Junín, Buenos Aires 6000, Argentina; Comisión de Investigaciones Científicas, CIC, La Plata, Buenos Aires 1900, Argentina
| | - Miguel E Mejía
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Vuelta de Obligado 2490, CABA 1428, Argentina
| | - Bibiana E Dallard
- Instituto de Ciencias Veterinarias del Litoral (ICIVET-Litoral), Universidad Nacional del Litoral - Consejo Nacional de Investigaciones Científicas y Tecnológicas, (UNL-CONICET), Argentina; Laboratorio de Biología Celular y Molecular Aplicada, Facultad de Ciencias Veterinarias, Universidad Nacional del Litoral, Argentina, Universidad Nacional del Litoral - Consejo Nacional de Investigaciones Cientí∼ficas y Tecnoló∼gicas, (UNL-CONICET), Argentina
| | - Eleonora Sorianello
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Vuelta de Obligado 2490, CABA 1428, Argentina
| | - Damasia Becu-Villalobos
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Vuelta de Obligado 2490, CABA 1428, Argentina
| | - Isabel Lacau-Mengido
- Instituto de Biología y Medicina Experimental, IBYME-CONICET, Vuelta de Obligado 2490, CABA 1428, Argentina
| | - Carolina Cristina
- Centro de Investigaciones Básicas y Aplicadas, Universidad Nacional del Noroeste de la Provincia de Buenos Aires, Junín, Buenos Aires 6000, Argentina; Centro de Investigaciones y Transferencia del Noroeste de la Provincia de Buenos Aires, CITNOBA, UNNOBA - UNSAdA - CONICET, Monteagudo 2772, Pergamino, Buenos Aires 2700, Argentina.
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T C D, N K N, Pushparaj C, Narayanasamy A, Manickam P, Thiruvenkataswamy S, Sennimalai R. Novel therapeutic approaches targeting cancer stem cells: Unveiling new frontiers in breast cancer treatment. Pathol Res Pract 2025; 266:155800. [PMID: 39808859 DOI: 10.1016/j.prp.2024.155800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 12/13/2024] [Accepted: 12/25/2024] [Indexed: 01/16/2025]
Abstract
Breast cancer remains the leading cause of mortality among women with cancer. This article delves into the intricate relationship between breast cancer and cancer stem cells (CSCs), emphasizing advanced methods for their identification and isolation. The key isolation techniques, such as the mammosphere formation assay, surface marker identification, Side Population assay, and Aldehyde Dehydrogenase assay, are critically examined. Furthermore, the review analyzes CSC-specific molecular signaling pathways, focusing on actionable targets like CD44/CD24, Nanog, and Oct4. The potential of targeted therapies and small molecules that disrupt these pathways is explored. Additionally, the review highlights immunotherapy strategies against CSCs, focusing on resistance mechanisms and the critical role of precision medicine. The study investigates how precision medicine enhances therapeutic outcomes by targeting specific CSC biomarkers. This comprehensive analysis offers insights into recent advancements and emerging strategies in breast cancer treatment, pointing toward future therapeutic innovations.
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Affiliation(s)
- Deeptha T C
- Department of Zoology, PSGR Krishnammal College for Women, Coimbatore, India
| | - Nabeela N K
- Department of Zoology, PSGR Krishnammal College for Women, Coimbatore, India
| | | | - Arul Narayanasamy
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, India
| | - Paulpandi Manickam
- Disease Proteomics Laboratory, Department of Zoology, Bharathiar University, Coimbatore, India
| | | | - Ramya Sennimalai
- Department of Zoology (PG), Vellalar College for Women, Erode, India.
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Cataldo D, Aravena G, Escobar A, Tapia JC, Peralta OA, Torres CG. Effect of Melatonin on Chemoresistance Exhibited by Spheres Derived from Canine Mammary Carcinoma Cells. Animals (Basel) 2024; 14:1229. [PMID: 38672378 PMCID: PMC11047318 DOI: 10.3390/ani14081229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 03/12/2024] [Accepted: 04/12/2024] [Indexed: 04/28/2024] Open
Abstract
Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary tumor microenvironment, there is a cell subpopulation called cancer stem cells (CSCs), which are capable of forming spheres in vitro and resisting anti-tumor treatments, partly explaining the recurrence of some tumors. Previously, it has been described that spheres derived from canine mammary carcinoma cells CF41.Mg and REM 134 exhibit stemness characteristics. Melatonin has shown anti-tumor effects on mammary tumor cells; however, its effects have been poorly evaluated in canine mammary CSCs. This study aimed to analyze the effect of melatonin on the chemoresistance exhibited by stem-like neoplastic cells derived from canine mammary carcinoma to cytotoxic drugs such as doxorubicin and mitoxantrone. CF41.Mg and REM 134 cells were cultured in high-glucose DMEM supplemented with fetal bovine serum and L-glutamine. The spheres were cultured in ultra-low attachment plates in DMEM/F12 medium without fetal bovine serum and with different growth factors. The CD44+/CD24-/low phenotype was analyzed by flow cytometry. The viability of sphere-derived cells (MTS reduction) was studied in the presence of melatonin (0.1 or 1 mM), doxorubicin, mitoxantrone, and luzindole. In addition, the gene (RT-qPCR) of the multidrug resistance bombs MDR1 and ABCG2 were analyzed in the presence of melatonin. Both cell types expressed the MT1 gene, which encodes the melatonin receptor MT1. Melatonin 1 mM does not modify the CD44+/CD24-/low phenotype; however, the hormone reduced viability (p < 0.0001) only in CF41.Mg spheres, without inducing an additive effect when co-incubated with cytotoxic drugs. These effects were independent of the binding of the hormone to its receptor MT1, since, by pharmacologically inhibiting them, the effect of melatonin was not blocked. In CF41.Mg spheres, the relative gene expression of ABCG2 and MDR1 was decreased in response to the hormone (p < 0.001). These results indicate that melatonin negatively modulates the cell survival of spheres derived from CF41.Mg cells, in a way that is independent of its MT1 receptor. These effects did not counteract the resistance to doxorubicin and mitoxantrone, even though the hormone negatively regulates the gene expression of MDR1 and ABCG2.
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Affiliation(s)
- Dania Cataldo
- Centralized Laboratory of Veterinary Research, Faculty of Animal and Veterinary Sciences, Universidad de Chile, Santiago 8820808, Chile; (D.C.); (G.A.)
- Laboratory of Biomedicine, Department of Clinical Sciences, Faculty of Animal and Veterinary Sciences, Universidad de Chile, Santiago 8820808, Chile
| | - Guillermo Aravena
- Centralized Laboratory of Veterinary Research, Faculty of Animal and Veterinary Sciences, Universidad de Chile, Santiago 8820808, Chile; (D.C.); (G.A.)
| | - Alejandro Escobar
- Laboratory of Cell and Molecular Biology, Dental Sciences Research Institute, Faculty of Dentistry, Universidad de Chile, Santiago 8380453, Chile;
| | - Julio C. Tapia
- Cell and Molecular Biology Program, Biomedical Sciences Institute, Faculty of Medicine, Universidad de Chile, Santiago 8380453, Chile;
| | - Oscar A. Peralta
- School of Veterinary Medicine, Pontificia Universidad Catolica de Chile, Santiago 7820435, Chile;
| | - Cristian G. Torres
- Centralized Laboratory of Veterinary Research, Faculty of Animal and Veterinary Sciences, Universidad de Chile, Santiago 8820808, Chile; (D.C.); (G.A.)
- Laboratory of Biomedicine, Department of Clinical Sciences, Faculty of Animal and Veterinary Sciences, Universidad de Chile, Santiago 8820808, Chile
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Saliu TP, Seneviratne NN, Faizan M, Rajagopalan U, Perera DC, Adhikari A, Senathilake KS, Galhena P, Tennekoon KH, Samarakoon SR. In silico identification and in vitro validation of alpha-hederin as a potent inhibitor of Wnt/β-catenin signaling pathway in breast cancer stem cells. In Silico Pharmacol 2024; 12:31. [PMID: 38617708 PMCID: PMC11014832 DOI: 10.1007/s40203-024-00199-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 02/19/2024] [Indexed: 04/16/2024] Open
Abstract
Cancer stem cells (CSCs) play a vital role in metastasis, recurrence and chemoresistance in breast cancer. β-catenin, which is a frequently over activated protein in CSCs, binds to T-cell factor/lymphoid enhancer factor (Tcf/Lef) family transcription factors leading to ectopic expression of Wnt pathway responsive genes necessary for the maintenance and action of CSCs. With the aim of identifying a small molecules that can effectively eliminate CSCs, molecular docking studies were performed against the Tcf/Lef binding hotspot on β-catenin using a library of 100 natural or synthetic small molecules. Small molecule ligands giving docking energy better than - 7 kcal/mol were further investigated by binding interactions analysis and molecular dynamics (MD) simulations. These compounds were then investigated in vitro, for cytotoxicity against CSCs isolated from MDA-MB-231 triple negative breast cancer cells. Alpha-hederin (AH) was identified as the only compound in the selected library that has cytotoxicity against breast CSCs. AH was further investigated for it's ability to regulate Wnt pathway target genes (Cyclin D1 and CD44)and the tumor suppressor p53by real-time quantitative PCR. Absorption, distribution, metabolism, excretion and toxicity properties of the AH was predicted in silico. AH significantly down regulated the transcription of Cyclin D1 and CD44 while up-regulating the transcription of p53. AH was predicted to have acceptable drug likeness. Although AH is currently known to inhibit the growth of various cancer cells in vitro, present study demonstrated for the first time that it is a potent inhibitor of Wnt/β-catenin signaling pathway and induce apoptosis in breast CSCs.
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Affiliation(s)
- Tolulope Peter Saliu
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Nirwani Natasha Seneviratne
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Mishal Faizan
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Umapriyatharshini Rajagopalan
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Damith Chathuranga Perera
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Achyut Adhikari
- Central Department of Chemistry, Tribhuvan University, Kirtipur, Kathmandu, Nepal
| | - Kanishka Sithira Senathilake
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Prasanna Galhena
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Kamani Hemamala Tennekoon
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
| | - Sameera Ranganath Samarakoon
- Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo, 90, CumaratungaMunidasaMawatha, Colombo, 03 Sri Lanka
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Umapathy VR, Dhanavel A, Kesavan R, Natarajan PM, S B, P V. Anticancer Potential of the Principal Constituent of Piper nigrum, Piperine: A Comprehensive Review. Cureus 2024; 16:e54425. [PMID: 38405638 PMCID: PMC10894018 DOI: 10.7759/cureus.54425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/18/2024] [Indexed: 02/27/2024] Open
Abstract
Black pepper's main component, piperine, is a phytochemical that gives the spice its distinctively pungent flavor, which has made it a staple in human diets for decades and a widely used food item. In addition to its use as a culinary component and preservation agent, it is also employed in traditional medicine for a diverse range of objectives, a practice that has been substantiated by existing scientific investigations on its physiological impacts in the majority of instances. Piperine contains various bioactive effects, such as antibacterial activity, in addition to several physiological benefits that could help overall human health, such as immunomodulatory, hepatoprotective, antioxidant, antimetastatic, anticancer, and many more properties that have been established. Clinical trials revealed that this phytochemical has exceptional antioxidant, anticancer, and drug availability-enhancing properties, as well as immunomodulatory potential. The different components of evidence indicate the therapeutic potential of piperine and underscore the importance of incorporating it into both broad health-promoting interventions and supplementary treatment pharmaceutical formulations. This inclusion can enhance the bioavailability of other therapeutic medications, including those used in chemotherapy.
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Affiliation(s)
- Vidhya Rekha Umapathy
- Public Health Dentistry, Meenakshi Ammal Dental College and Hospital, Meenakshi Academy of Higher Education and Research (MAHER), Chennai, IND
| | - Anandhi Dhanavel
- Biochemistry, Meenakshi Academy of Higher Education and Research (MAHER), Chennai, IND
| | - R Kesavan
- Public Health Dentistry, Thai Moogambigai Dental College and Hospital, Chennai, IND
| | | | - Bhuminathan S
- Public Health Dentistry, Sree Balaji Dental College & Hospital, Chennai, IND
| | - Vijayalakshmi P
- Biotechnology, Holy Cross College (Autonomous) Tiruchirappalli, Tiruchirappalli, IND
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Singh S. Review on Natural Agents as Aromatase Inhibitors: Management of Breast Cancer. Comb Chem High Throughput Screen 2024; 27:2623-2638. [PMID: 37861041 DOI: 10.2174/0113862073269599231009115338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 08/16/2023] [Accepted: 09/21/2023] [Indexed: 10/21/2023]
Abstract
Breast cancer is a prevalent type of cancer that is typically hormone-dependent, caused by estrogen. Aromatase inhibitors are frequently utilised in the treatment of hormonereceptor- positive breast cancer because they prevent the enzyme aromatase from converting androgens to estrogens. Natural medicines with aromatase inhibitory characteristics have attracted interest as potential alternatives or complementary therapy to manufactured medications. This review discusses the function of natural agents as aromatase inhibitors in treating breast cancer. A variety of natural compounds have been investigated for their capacity to inhibit aromatase activity and lower estrogen levels. These agents include resveratrol from red wine and grapes, curcumin from turmeric extract and green teahigh in catechins, and other flavonoids such as genistein, luteolin and quercetin. It has been demonstrated that by decreasing estrogen synthesis, they can slow the growth of breast cancer cells that are dependent on estrogen. However, the clinical evidence supporting their efficacy and safety in breast cancer treatment is inadequate. More research is required to investigate the therapeutic potential of natural medicines, such as aromatase inhibitors, in treating breast cancer. The clinical trials are required to assess their efficacy, appropriate doses, and potential interactions with other therapies. In conclusion, natural aromatase inhibitory drugs are promising adjuncts in the treatment of hormone receptor-positive breast cancer. Their clinical value and safety profile, however, require additional investigation.
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Affiliation(s)
- Sonia Singh
- Institute of Pharmaceutical Research, GLA University Mathura, U.P: 281406, India
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Zhong C, Wang G, Guo M, Zhu N, Chen X, Yan Y, Li N, Yu W. The Role of Tumor Stem Cells in Colorectal Cancer Drug Resistance. Cancer Control 2024; 31:10732748241274196. [PMID: 39215442 PMCID: PMC11367616 DOI: 10.1177/10732748241274196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 07/09/2024] [Accepted: 07/23/2024] [Indexed: 09/04/2024] Open
Abstract
Background: Colorectal cancer is a major cause of mortality among the prevalent malignant tumors of the gastrointestinal tract. Although chemotherapy is a standard treatment for colorectal cancer, its efficacy is limited by chemoresistance. Recent studies have investigated targeting tumor stem cells as a potential new therapeutic approach for addressing chemoresistance in colorectal cancer. Colorectal cancer frequently relapses, with tumor stem cells often representing one of the leading causes of treatment failure. Purpose: Understanding drug resistance in colorectal cancer stem cells is crucial for improving treatment outcomes. By focusing on developing targeted therapies that specifically address drug resistance in colorectal cancer stem cells, there is potential to make significant advancements in the treatment of colorectal cancer.This approach may lead to more effective and lasting outcomes in patients battling colorectal cancer. Research Design: In this review, a comprehensive overview of recent research on colorectal cancer stem cell treatment resistance is presented.Results: Elucidating the key underlying mechanisms. This review also highlights the potential benefits of targeted therapies in overcoming colorectal cancer resistance to treatment. Conclusions: CCSCs are key players in drug resistance of CRC, indicating their potential as targets for effective therapy. Elucidating their role in this process could aid in discovering tailored treatment strategies.The significance of signaling pathways, TME, and miRNA in regulating drug resistance in CCSCs is been highlighted.
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Affiliation(s)
- Chen Zhong
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Guojuan Wang
- Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, China
| | - Min Guo
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Naicheng Zhu
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Xiudan Chen
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Yuwei Yan
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Nanxin Li
- Jiangxi University of Chinese Medicine, Nanchang, China
| | - Wenyan Yu
- Jiangxi University of Chinese Medicine, Nanchang, China
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Mia MAR, Dey D, Sakib MR, Biswas MY, Prottay AAS, Paul N, Rimti FH, Abdullah Y, Biswas P, Iftehimul M, Paul P, Sarkar C, El-Nashar HAS, El-Shazly M, Islam MT. The efficacy of natural bioactive compounds against prostate cancer: Molecular targets and synergistic activities. Phytother Res 2023; 37:5724-5754. [PMID: 37786304 DOI: 10.1002/ptr.8017] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 08/17/2023] [Accepted: 09/05/2023] [Indexed: 10/04/2023]
Abstract
Globally, prostate cancer (PCa) is regarded as a challenging health issue, and the number of PCa patients continues to rise despite the availability of effective treatments in recent decades. The current therapy with chemotherapeutic drugs has been largely ineffective due to multidrug resistance and the conventional treatment has restricted drug accessibility to malignant tissues, necessitating a higher dosage resulting in increased cytotoxicity. Plant-derived bioactive compounds have recently attracted a great deal of attention in the field of PCa treatment due to their potent effects on several molecular targets and synergistic effects with anti-PCa drugs. This review emphasizes the molecular mechanism of phytochemicals on PCa cells, the synergistic effects of compound-drug interactions, and stem cell targeting for PCa treatment. Some potential compounds, such as curcumin, phenethyl-isothiocyanate, fisetin, baicalein, berberine, lutein, and many others, exert an anti-PCa effect via inhibiting proliferation, metastasis, cell cycle progression, and normal apoptosis pathways. In addition, multiple studies have demonstrated that the isolated natural compounds: d-limonene, paeonol, lanreotide, artesunate, and bicalutamide have potential synergistic effects. Further, a significant number of natural compounds effectively target PCa stem cells. However, further high-quality studies are needed to firmly establish the clinical efficacy of these phytochemicals against PCa.
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Affiliation(s)
- Md Abdur Rashid Mia
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, Bangladesh
| | - Dipta Dey
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Musfiqur Rahman Sakib
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Md Yeaman Biswas
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology (JUST), Jashore, Bangladesh
| | - Abdullah Al Shamsh Prottay
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Niloy Paul
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Fahmida Hoque Rimti
- Bachelor of Medicine and Surgery, Chittagong Medical College, Chawkbazar, Bangladesh
| | - Yusuf Abdullah
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Partha Biswas
- Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology (JUST), Jashore, Bangladesh
| | - Md Iftehimul
- Department of Fisheries and Marine Bioscience, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Priyanka Paul
- Department of Biochemistry and Molecular Biology, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Chandan Sarkar
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
| | - Heba A S El-Nashar
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mohamed El-Shazly
- Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University, Gopalgonj, Bangladesh
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Tacchini M, Sacchetti G, Guerrini A, Paganetto G. Mycochemicals against Cancer Stem Cells. Toxins (Basel) 2023; 15:360. [PMID: 37368660 DOI: 10.3390/toxins15060360] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 05/08/2023] [Accepted: 05/22/2023] [Indexed: 06/29/2023] Open
Abstract
Since ancient times, mushrooms have been considered valuable allies of human well-being both from a dietary and medicinal point of view. Their essential role in several traditional medicines is explained today by the discovery of the plethora of biomolecules that have shown proven efficacy for treating various diseases, including cancer. Numerous studies have already been conducted to explore the antitumoural properties of mushroom extracts against cancer. Still, very few have reported the anticancer properties of mushroom polysaccharides and mycochemicals against the specific population of cancer stem cells (CSCs). In this context, β-glucans are relevant in modulating immunological surveillance against this subpopulation of cancer cells within tumours. Small molecules, less studied despite their spread and assortment, could exhibit the same importance. In this review, we discuss several pieces of evidence of the association between β-glucans and small mycochemicals in modulating biological mechanisms which are proven to be involved with CSCs development. Experimental evidence and an in silico approach are evaluated with the hope of contributing to future strategies aimed at the direct study of the action of these mycochemicals on this subpopulation of cancer cells.
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Affiliation(s)
- Massimo Tacchini
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Gianni Sacchetti
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Alessandra Guerrini
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
| | - Guglielmo Paganetto
- Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
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Hao L, Zhang J, Liu Z, Lin X, Guo J. Epitranscriptomics in the development, functions, and disorders of cancer stem cells. Front Oncol 2023; 13:1145766. [PMID: 37007137 PMCID: PMC10063963 DOI: 10.3389/fonc.2023.1145766] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 02/10/2023] [Indexed: 03/19/2023] Open
Abstract
Biomolecular modifications play an important role in the development of life, and previous studies have investigated the role of DNA and proteins. In the last decade, with the development of sequencing technology, the veil of epitranscriptomics has been gradually lifted. Transcriptomics focuses on RNA modifications that affect gene expression at the transcriptional level. With further research, scientists have found that changes in RNA modification proteins are closely linked to cancer tumorigenesis, progression, metastasis, and drug resistance. Cancer stem cells (CSCs) are considered powerful drivers of tumorigenesis and key factors for therapeutic resistance. In this article, we focus on describing RNA modifications associated with CSCs and summarize the associated research progress. The aim of this review is to identify new directions for cancer diagnosis and targeted therapy.
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Affiliation(s)
- Linlin Hao
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Jian Zhang
- School of Life Sciences, Department of Biology, Southern University of Science and Technology, Shenzhen, China
| | - Zhongshan Liu
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Xia Lin
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
| | - Jie Guo
- Department of Tumor Radiotherapy, The Second Hospital of Jilin University, Changchun, China
- *Correspondence: Jie Guo,
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11
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Farahani MK, Bitaraf FS, Atashi A, Jabbarpour Z. Evaluation of anticancer effects of frankincense on breast cancer stem-like cells. Cancer Rep (Hoboken) 2023; 6:e1693. [PMID: 36806721 PMCID: PMC9939999 DOI: 10.1002/cnr2.1693] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/24/2022] [Accepted: 07/27/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Relapse and metastasis in breast cancer are linked to cancer stem cells (CSCs) resistant to anticancer therapies. The presence of cancer stem-like cells (CSLCs) and their ability to self-renew is determined by in vitro spheroid formation. AIMS Many studies have found that frankincense has anticancer impacts, although these effects on breast CSLCs have never been evaluated. METHODS AND RESULTS A population of heterogeneous breast tumor cells was extracted from the tumor mass after generating an animal model of triple-negative breast cancer (TNBC). Spheroid formation was used as an in vitro assay to determine the existence of CSLCs in these cells. MTT assay was used to determine frankincense's cytotoxic activity. An annexin V- propidium iodide (PI) staining and scratch test were used to assess the induction of apoptosis and antimetastatic effects of frankincense. The frankincense extract has significant cytotoxic and apoptotic effects on breast CSLCs. Although, the breast CSLCs are more resistant to these impacts than other breast cancer cells. CONCLUSION Our study is the first report that indicates that frankincense extract has anticancer properties in breast CSLCs. Compared to many anticancer chemicals, which have limited potential to battle cancer stem cells, frankincense is an appropriate option to combat breast CSCs.
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Affiliation(s)
| | - Fateme Sadat Bitaraf
- Department of Medical Biotechnology, School of MedicineShahroud University of Medical SciencesShahroudIran
| | - Amir Atashi
- Department of Medical Laboratory Sciences, School of ParamedicalShahroud University of Medical SciencesShahroudIran
| | - Zahra Jabbarpour
- Gene Therapy Research Center, Digestive Disease Research InstituteTehran University of Medical SciencesTehranIran
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12
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Kola P, Nagesh PKB, Roy PK, Deepak K, Reis RL, Kundu SC, Mandal M. Innovative nanotheranostics: Smart nanoparticles based approach to overcome breast cancer stem cells mediated chemo- and radioresistances. WILEY INTERDISCIPLINARY REVIEWS. NANOMEDICINE AND NANOBIOTECHNOLOGY 2023:e1876. [PMID: 36600447 DOI: 10.1002/wnan.1876] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 11/29/2022] [Accepted: 12/09/2022] [Indexed: 01/06/2023]
Abstract
The alarming increase in the number of breast cancer patients worldwide and the increasing death rate indicate that the traditional and current medicines are insufficient to fight against it. The onset of chemo- and radioresistances and cancer stem cell-based recurrence make this problem harder, and this hour needs a novel treatment approach. Competent nanoparticle-based accurate drug delivery and cancer nanotheranostics like photothermal therapy, photodynamic therapy, chemodynamic therapy, and sonodynamic therapy can be the key to solving this problem due to their unique characteristics. These innovative formulations can be a better cargo with fewer side effects than the standard chemotherapy and can eliminate the stability problems associated with cancer immunotherapy. The nanotheranostic systems can kill the tumor cells and the resistant breast cancer stem cells by novel mechanisms like local hyperthermia and reactive oxygen species and prevent tumor recurrence. These theranostic systems can also combine with chemotherapy or immunotherapy approaches. These combining approaches can be the future of anticancer therapy, especially to overcome the breast cancer stem cells mediated chemo- and radioresistances. This review paper discusses several novel theranostic systems and smart nanoparticles, their mechanism of action, and their modifications with time. It explains their relevance and market scope in the current era. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.
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Affiliation(s)
- Prithwish Kola
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | | | - Pritam Kumar Roy
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - K Deepak
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Rui Luis Reis
- 3Bs Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimaraes, Portugal
| | - Subhas C Kundu
- 3Bs Research Group, I3Bs-Research Institute on Biomaterials, Biodegradables and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, Guimaraes, Portugal
| | - Mahitosh Mandal
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, Kharagpur, India
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13
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Chaudhuri A, Kumar DN, Dehari D, Singh S, Kumar P, Bolla PK, Kumar D, Agrawal AK. Emergence of Nanotechnology as a Powerful Cavalry against Triple-Negative Breast Cancer (TNBC). Pharmaceuticals (Basel) 2022; 15:542. [PMID: 35631368 PMCID: PMC9143332 DOI: 10.3390/ph15050542] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 04/26/2022] [Accepted: 04/26/2022] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is considered one of the un-manageable types of breast cancer, involving devoid of estrogen, progesterone, and human epidermal growth factor receptor 2 (HER 2) receptors. Due to their ability of recurrence and metastasis, the management of TNBC remains a mainstay challenge, despite the advancements in cancer therapies. Conventional chemotherapy remains the only treatment regimen against TNBC and suffers several limitations such as low bioavailability, systemic toxicity, less targetability, and multi-drug resistance. Although various targeted therapies have been introduced to manage the hardship of TNBC, they still experience certain limitations associated with the survival benefits. The current research thus aimed at developing and improving the strategies for effective therapy against TNBC. Such strategies involved the emergence of nanoparticles. Nanoparticles are designated as nanocavalries, loaded with various agents (drugs, genes, etc.) to battle the progression and metastasis of TNBC along with overcoming the limitations experienced by conventional chemotherapy and targeted therapy. This article documents the treatment regimens of TNBC along with their efficacy towards different subtypes of TNBC, and the various nanotechnologies employed to increase the therapeutic outcome of FDA-approved drug regimens.
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Affiliation(s)
- Aiswarya Chaudhuri
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Dulla Naveen Kumar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Deepa Dehari
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Sanjay Singh
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
- Babasaheb Bhimrao Ambedkar University, Lucknow 226025, India
| | - Pradeep Kumar
- Department of Pharmacy and Pharmacology, School of Therapeutic Sciences, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg 2193, South Africa;
| | - Pradeep Kumar Bolla
- Department of Biomedical Engineering, College of Engineering, The University of Texas at El Paso, 500 W. University Ave, El Paso, TX 79968, USA;
| | - Dinesh Kumar
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
| | - Ashish Kumar Agrawal
- Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), Varanasi 221005, India; (A.C.); (D.N.K.); (D.D.); (S.S.); (D.K.)
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14
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Wharton’s Jelly-Derived Mesenchymal Stem Cells with High Aurora Kinase A Expression Show Improved Proliferation, Migration, and Therapeutic Potential. Stem Cells Int 2022; 2022:4711499. [PMID: 35450345 PMCID: PMC9017458 DOI: 10.1155/2022/4711499] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 03/11/2022] [Indexed: 11/25/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are effective therapeutic agents that contribute to tissue repair and regeneration by secreting various factors. However, donor-dependent variations in MSC proliferation and therapeutic potentials result in variable production yields and clinical outcomes, thereby impeding MSC-based therapies. Hence, selection of MSCs with high proliferation and therapeutic potentials would be important for effective clinical application of MSCs. This study is aimed at identifying the upregulated genes in human Wharton's jelly-derived MSCs (WJ-MSCs) with high proliferation potential using mRNA sequencing. Aurora kinase A (AURKA) and dedicator of cytokinesis 2 (DOCK2) were selected as the upregulated genes, and their effects on proliferation, migration, and colony formation of the WJ-MSCs were verified using small interfering RNA (siRNA) techniques. mRNA expression levels of both the genes were positively correlated with the proliferation capacity of WJ-MSCs. Moreover, AURKA from human WJ-MSCs regulated the antiapoptotic effect of skeletal muscle cells by upregulating the chemokine (C motif) ligand (XCL1); this was further confirmed in the mdx mouse model. Taken together, the results indicated that AURKA and DOCK2 can be used as potential biomarkers for proliferation and migration of human WJ-MSCs. In particular, human WJ-MSCs with high expression of AURKA might have therapeutic efficacy against muscle diseases, such as Duchenne muscular dystrophy (DMD).
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15
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Han Y, Villarreal-Ponce A, Gutierrez G, Nguyen Q, Sun P, Wu T, Sui B, Berx G, Brabletz T, Kessenbrock K, Zeng YA, Watanabe K, Dai X. Coordinate control of basal epithelial cell fate and stem cell maintenance by core EMT transcription factor Zeb1. Cell Rep 2022; 38:110240. [PMID: 35021086 PMCID: PMC9894649 DOI: 10.1016/j.celrep.2021.110240] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 09/30/2021] [Accepted: 12/16/2021] [Indexed: 02/04/2023] Open
Abstract
Maintenance of undifferentiated, long-lived, and often quiescent stem cells in the basal compartment is important for homeostasis and regeneration of multiple epithelial tissues, but the molecular mechanisms that coordinately control basal cell fate and stem cell quiescence are elusive. Here, we report an epithelium-intrinsic requirement for Zeb1, a core transcriptional inducer of epithelial-to-mesenchymal transition, for mammary epithelial ductal side branching and for basal cell regenerative capacity. Our findings uncover an evolutionarily conserved role of Zeb1 in promoting basal cell fate over luminal differentiation. We show that Zeb1 loss results in increased basal cell proliferation at the expense of quiescence and self-renewal. Moreover, Zeb1 cooperates with YAP to activate Axin2 expression, and inhibition of Wnt signaling partially restores stem cell function to Zeb1-deficient basal cells. Thus, Zeb1 is a transcriptional regulator that maintains both basal cell fate and stem cell quiescence, and it functions in part through suppressing Wnt signaling.
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Affiliation(s)
- Yingying Han
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA,These authors contributed equally
| | - Alvaro Villarreal-Ponce
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA,These authors contributed equally
| | - Guadalupe Gutierrez
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA
| | - Quy Nguyen
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA
| | - Peng Sun
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA
| | - Ting Wu
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China
| | - Benjamin Sui
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA
| | - Geert Berx
- Molecular and Cellular Oncology Lab, Department of Biomedical Molecular Biology, Ghent University, Technologiepark 71, 9052 Zwijnaarde, Belgium,Cancer Research Institute Ghent, Ghent, Belgium
| | - Thomas Brabletz
- Department of Experimental Medicine, Nikolaus-Fiebiger-Center for Molecular Medicine I, University, Erlangen-Nuernberg Glueckstr. 6, 91054 Erlangen, Germany
| | - Kai Kessenbrock
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA
| | - Yi Arial Zeng
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China
| | - Kazuhide Watanabe
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA,RIKEN Center for Integrative Medical Sciences, Yokohama 230-0045, Japan
| | - Xing Dai
- Department of Biological Chemistry, School of Medicine, D250 Med Sci I, University of California, Irvine, Irvine, CA 92697-1700, USA,Lead contact,Correspondence:
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16
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Abstract
Somatic stem cells are distinguished by their capacity to regenerate themselves and also to produce daughter cells that will differentiate. Self-renewal is achieved through the process of asymmetric cell division which helps to sustain tissue morphogenesis as well as maintain homeostasis. Asymmetric cell division results in the development of two daughter cells with different fates after a single mitosis. Only one daughter cell maintains "stemness" while the other differentiates and achieves a non-stem cell fate. Stem cells also have the capacity to undergo symmetric division of cells that results in the development of two daughter cells which are identical. Symmetric division results in the expansion of the stem cell population. Imbalances and deregulations in these processes can result in diseases such as cancer. Adult mammary stem cells (MaSCs) are a group of cells that play a critical role in the expansion of the mammary gland during puberty and any subsequent pregnancies. Furthermore, given the relatively long lifespans and their capability to undergo self-renewal, adult stem cells have been suggested as ideal candidates for transformation events that lead to the development of cancer. With the possibility that MaSCs can act as the source cells for distinct breast cancer types; understanding their regulation is an important field of research. In this review, we discuss asymmetric cell division in breast/mammary stem cells and implications on further research. We focus on the background history of asymmetric cell division, asymmetric cell division monitoring techniques, identified molecular mechanisms of asymmetric stem cell division, and the role asymmetric cell division may play in breast cancer.
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Affiliation(s)
| | - Brian W Booth
- Department of Bioengineering, Head-Cellular Engineering Laboratory, 401-1 Rhodes Engineering Research Center, Clemson University, Clemson, SC, 29634, USA.
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17
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Hafez HG, Mohareb RM, Salem SM, Matloub AA, Eskander EF, Ahmed HH. Molecular Mechanisms Underlying the Anti-Breast Cancer Stem Cell Activity of Pterocladia capillacea and Corallina officinalis Polysaccharides. Anticancer Agents Med Chem 2021; 22:1213-1225. [PMID: 34315394 DOI: 10.2174/1871520621666210727122756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 04/26/2021] [Accepted: 05/31/2021] [Indexed: 12/24/2022]
Abstract
OBJECTIVE This study aimed to appraise the activity of Pterocladia capillacea and Corallina officinalis polysaccharides against breast cancer stem cells (BCSCs). P. capillacea and C. officinalis polysaccharides were characterized to be sulfated polysaccharide-protein complexes. METHODS Cytotoxicity of the polysaccharides against MDA-MB-231 and MCF-7 cell lines along with their impact on CD44+/CD24- and aldehyde dehydrogenase 1(ALDH1) positive BCSC population were determined. Their effect on gene expression of CSC markers, Wnt/β-catenin and Notch signaling pathways was evaluated. RESULTS P. capillacea and C. officinalis polysaccharides inhibited the growth of breast cancer cells and reduced BCSC subpopulation. P. capillacea polysaccharides significantly down-regulated OCT4, SOX2, ALDH1A3 and vimentin in MDA-MB-231 as well as in MCF-7 cells except for vimentin that was up-regulated in MCF-7 cells. C. officinalis polysaccharides exhibited similar effects except for OCT4 that was up-regulated in MDA-MB-231 cells. Significant suppression of Cyclin D1 gene expression was noted in MDA-MB-231 and MCF-7 cells treated with P. capillacea or C. officinalis polysaccharides. β-catenin and c-Myc genes were significantly down-regulated in MDA-MB-231 cells treated with C. officinalis and P. capillacea polysaccharides, respectively, while being up-regulated in MCF-7 cells treated with either of them. Additionally, P. capillacea and C. officinalis polysaccharides significantly down-regulated Hes1 gene in MCF-7 cells despite increasing Notch1 gene expression level. However, significant down-regulation of Notch1 gene was observed in MDA-MB-231 cells treated with P. capillacea polysaccharides. CONCLUSION Collectively, this study provides evidence for the effectiveness of P. capillacea and C. officinalis polysaccharides in targeting BCSCs through interfering with substantial signaling pathways contributing to their functionality.
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Affiliation(s)
- Hebatallah G Hafez
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Rafat M Mohareb
- Chemistry Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Sohair M Salem
- Molecular Genetics and Enzymology Department, National Research Centre, Dokki, Giza, Egypt
| | - Azza A Matloub
- Department of Pharmacognosy, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Emad F Eskander
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
| | - Hanaa H Ahmed
- Hormones Department, Medical Research Division, National Research Centre, Dokki, Giza, Egypt
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18
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Wszoła M, Nitarska D, Cywoniuk P, Gomółka M, Klak M. Stem Cells as a Source of Pancreatic Cells for Production of 3D Bioprinted Bionic Pancreas in the Treatment of Type 1 Diabetes. Cells 2021; 10:1544. [PMID: 34207441 PMCID: PMC8234129 DOI: 10.3390/cells10061544] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/10/2021] [Accepted: 06/15/2021] [Indexed: 12/14/2022] Open
Abstract
Type 1 diabetes (T1D) is the third most common autoimmune disease which develops due to genetic and environmental risk factors. Often, intensive insulin therapy is insufficient, and patients require a pancreas or pancreatic islets transplant. However, both solutions are associated with many possible complications, including graft rejection. The best approach seems to be a donor-independent T1D treatment strategy based on human stem cells cultured in vitro and differentiated into insulin and glucagon-producing cells (β and α cells, respectively). Both types of cells can then be incorporated into the bio-ink used for 3D printing of the bionic pancreas, which can be transplanted into T1D patients to restore glucose homeostasis. The aim of this review is to summarize current knowledge about stem cells sources and their transformation into key pancreatic cells. Last, but not least, we comment on possible solutions of post-transplant immune response triggered stem cell-derived pancreatic cells and their potential control mechanisms.
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Affiliation(s)
- Michał Wszoła
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
- Polbionica Ltd., 01-793 Warsaw, Poland;
- Medispace Medical Centre, 01-044 Warsaw, Poland
| | | | - Piotr Cywoniuk
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
| | - Magdalena Gomółka
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
| | - Marta Klak
- Foundation of Research and Science Development, 01-793 Warsaw, Poland; (M.W.); (P.C.); (M.G.)
- Polbionica Ltd., 01-793 Warsaw, Poland;
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19
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Alantolactone inhibits cervical cancer progression by downregulating BMI1. Sci Rep 2021; 11:9251. [PMID: 33927214 PMCID: PMC8085045 DOI: 10.1038/s41598-021-87781-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Accepted: 03/10/2021] [Indexed: 01/31/2023] Open
Abstract
Cervical cancer is the second most common cancer in women. Despite advances in cervical cancer therapy, tumor recurrence and metastasis remain the leading causes of mortality. High expression of BMI1 is significantly associated with poor tumor differentiation, high clinical grade, and poor prognosis of cervical cancer, and is an independent prognostic factor in cervical carcinoma. Alantolactone (AL), a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. In this paper, we investigated the mechanism of AL in reducing the proliferation, migration, and invasion of HeLa and SiHa cervical cancer cells as well as its promotion of mitochondrial damage and autophagy. BMI1 silencing decreased epithelial-mesenchymal transformation-associated proteins and increased autophagy-associated proteins in HeLa cells. These effects were reversed by overexpression of BMI1 in HeLa cells. Thus, BMI1 expression is positively correlated with invasion and negatively correlated with autophagy in HeLa cells. Importantly, AL decreased the weight, volume, and BMI1 expression in HeLa xenograft tumors. Furthermore, the structure of BMI1 and target interaction of AL were virtually screened using the molecular docking program Autodock Vina; AL decreased the expression of N-cadherin, vimentin, and P62 and increased the expression of LC3B and Beclin-1 in xenograft tumors. Finally, expression of BMI1 increased the phosphorylation of STAT3, which is important for cell proliferation, survival, migration, and invasion. Therefore, we suggest that AL plays a pivotal role in inhibiting BMI1 in the tumorigenesis of cervical cancer and is a potential therapeutic agent for cervical cancer.
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20
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Lechner J, Schulz T, Lejeune B, von Baehr V. Jawbone Cavitation Expressed RANTES/CCL5: Case Studies Linking Silent Inflammation in the Jawbone with Epistemology of Breast Cancer. BREAST CANCER-TARGETS AND THERAPY 2021; 13:225-240. [PMID: 33859496 PMCID: PMC8044077 DOI: 10.2147/bctt.s295488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Accepted: 03/09/2021] [Indexed: 12/04/2022]
Abstract
Background The role of signaling pathways as part of the cell-cell communication within cancer progression becomes a crucial area. Chemokine RANTES (regulated upon activation, normal T-cell expressed and secreted), also known as the chemokine C-C motif ligand 5 (CCL5) (R/C), is a protein on which cancer research focus due to its link with aggressive cancer development. Objective Research on fatty-degenerative osteonecrosis in jawbone (FDOJ) shows striking overexpression of R/C in these areas. Here we try to elucidate a potential link between jawbone-derived R/C and breast cancer (BC) and compare these findings by immunohistochemical staining. Methods Thirty-nine FDOJ samples extracted from 39 BC patients and samples from 19 healthy control were analyzed for R/C expression using bead-based Luminex® analysis. R/C levels from 5 BC patients were measured in serum before and after FDOJ surgery. Bone density, histology, R/C expression, and immunohistochemistry were analysed in 4 clinical case studies. The R/C staining of two FDOJ BC patients is compared with the immunohistochemical staining of BC cell preparations. Results A high overexpression of R/C was seen in all FDOJ samples. R/C levels in serum were statistically downregulated after FDOJ surgery (p=0.0241). Discussion R/C induced “silent inflammation” in BC is widely discussed in scientific papers along with R/C triggering of different signaling pathways, which might be a key point in the development of BC. Conclusion Hypothesis that FDOJ may serve as a trigger of BC progression through R/C overexpression was set by the authors, who thus inspire clinicians to make aware of FDOJ throughout the dental and medical community in BC cases.
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21
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Zubair M, Wang S, Ali N. Advanced Approaches to Breast Cancer Classification and Diagnosis. Front Pharmacol 2021; 11:632079. [PMID: 33716731 PMCID: PMC7952319 DOI: 10.3389/fphar.2020.632079] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2020] [Accepted: 12/29/2020] [Indexed: 12/15/2022] Open
Abstract
The International Agency for Research on Cancer (IARC) has recently reported a 66% increase in the global number of cancer deaths since 1960. In the US alone, about one in eight women is expected to develop invasive breast cancer(s) (breast cancer) at some point in their lifetime. Traditionally, a BC diagnosis includes mammography, ultrasound, and some high-end molecular bioimaging. Unfortunately, these techniques detect BC at a later stage. So early and advanced molecular diagnostic tools are still in demand. In the past decade, various histological and immuno-molecular studies have demonstrated that BC is highly heterogeneous in nature. Its growth pattern, cytological features, and expression of key biomarkers in BC cells including hormonal receptor markers can be utilized to develop advanced diagnostic and therapeutic tools. A cancer cell's progression to malignancy exhibits various vital biomarkers, many of which are still underrepresented in BC diagnosis and treatment. Advances in genetics have also enabled the development of multigene assays to detect genetic heterogeneity in BC. However, thus far, the FDA has approved only four such biomarkers-cancer antigens (CA); CA 15-3, CA 27-29, Human epidermal growth factor receptor 2 (HER2), and circulating tumor cells (CTC) in assessing BC in body fluids. An adequately structured portable-biosensor with its non-invasive and inexpensive point-of-care analysis can quickly detect such biomarkers without significantly compromising its specificity and selectivity. Such advanced techniques are likely to discriminate between BC and a healthy patient by accurately measuring the cell shape, structure, depth, intracellular and extracellular environment, and lipid membrane compositions. Presently, BC treatments include surgery and systemic chemo- and targeted radiation therapy. A biopsied sample is then subjected to various multigene assays to predict the heterogeneity and recurrence score, thus guiding a specific treatment by providing complete information on the BC subtype involved. Thus far, we have seven prognostic multigene signature tests for BC providing a risk profile that can avoid unnecessary treatments in low-risk patients. Many comparative studies on multigene analysis projected the importance of integrating clinicopathological information with genomic-imprint analysis. Current cohort studies such as MINDACT, TAILORx, Trans-aTTOM, and many more, are likely to provide positive impact on long-term patient outcome. This review offers consolidated information on currently available BC diagnosis and treatment options. It further describes advanced biomarkers for the development of state-of-the-art early screening and diagnostic technologies.
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Affiliation(s)
- M. Zubair
- Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, United States
| | - S. Wang
- Department of Chemistry, University of Arkansas at Little Rock, Little Rock, AR, United States
| | - N. Ali
- Department of Biology, University of Arkansas at Little Rock, Little Rock, AR, United States
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22
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Thakur G, Kumar R, Kim SB, Lee SY, Lee SL, Rho GJ. Therapeutic Status and Available Strategies in Pancreatic Ductal Adenocarcinoma. Biomedicines 2021; 9:biomedicines9020178. [PMID: 33670230 PMCID: PMC7916947 DOI: 10.3390/biomedicines9020178] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/03/2021] [Accepted: 02/08/2021] [Indexed: 02/06/2023] Open
Abstract
One of the most severe and devastating cancer is pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) is one of the major pancreatic exocrine cancer with a poor prognosis and growing prevalence. It is the most deadly disease, with an overall five-year survival rate of 6% to 10%. According to various reports, it has been demonstrated that pancreatic cancer stem cells (PCSCs) are the main factor responsible for the tumor development, proliferation, resistance to anti-cancer drugs, and recurrence of tumors after surgery. PCSCs have encouraged new therapeutic methods to be explored that can specifically target cancer cells. Furthermore, stem cells, especially mesenchymal stem cells (MSCs), are known as influential anti-cancer agents as they function through anti-inflammatory, paracrine, cytokines, and chemokine's action. The properties of MSCs, such as migration to the site of infection and host immune cell activation by its secretome, seem to control the microenvironment of the pancreatic tumor. MSCs secretome exhibits similar therapeutic advantages as a conventional cell-based therapy. Moreover, the potential for drug delivery could be enhanced by engineered MSCs to increase drug bioactivity and absorption at the tumor site. In this review, we have discussed available therapeutic strategies, treatment hurdles, and the role of different factors such as PCSCs, cysteine, GPCR, PKM2, signaling pathways, immunotherapy, and NK-based therapy in pancreatic cancer.
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Affiliation(s)
- Gitika Thakur
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Raj Kumar
- Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan 173 234, Himachal Pradesh, India;
| | - Saet-Byul Kim
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sang-Yeob Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Sung-Lim Lee
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
| | - Gyu-Jin Rho
- Department of Theriogenology and Biotechnology, College of Veterinary Medicine and Research Institute of Life Science, Gyeongsang National University, Jinju 52828, Korea; (G.T.); (S.-B.K.); (S.-Y.L.); (S.-L.L.)
- Correspondence:
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Castelli V, Catanesi M, Alfonsetti M, Laezza C, Lombardi F, Cinque B, Cifone MG, Ippoliti R, Benedetti E, Cimini A, d’Angelo M. PPARα-Selective Antagonist GW6471 Inhibits Cell Growth in Breast Cancer Stem Cells Inducing Energy Imbalance and Metabolic Stress. Biomedicines 2021; 9:biomedicines9020127. [PMID: 33525605 PMCID: PMC7912302 DOI: 10.3390/biomedicines9020127] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 01/24/2021] [Accepted: 01/26/2021] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is the most frequent cancer and the second leading cause of death among women. Triple-negative breast cancer is the most aggressive subtype of breast cancer and is characterized by the absence of hormone receptors and human epithelial growth factor receptor 2. Cancer stem cells (CSCs) represent a small population of tumor cells showing a crucial role in tumor progression, metastasis, recurrence, and drug resistance. The presence of CSCs can explain the failure of conventional therapies to completely eradicate cancer. Thus, to overcome this limit, targeting CSCs may constitute a promising approach for breast cancer treatment, especially in the triple-negative form. To this purpose, we isolated and characterized breast cancer stem cells from a triple-negative breast cancer cell line, MDA-MB-231. The obtained mammospheres were then treated with the specific PPARα antagonist GW6471, after which, glucose, lipid metabolism, and invasiveness were analyzed. Notably, GW6471 reduced cancer stem cell viability, proliferation, and spheroid formation, leading to apoptosis and metabolic impairment. Overall, our findings suggest that GW6471 may be used as a potent adjuvant for gold standard therapies for triple-negative breast cancer, opening the possibility for preclinical and clinical trials for this class of compounds.
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Affiliation(s)
- Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Mariano Catanesi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Margherita Alfonsetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Chiara Laezza
- Institute of Endocrinology and Experimental Oncology G. Salvatore, CNR, 80131 Naples, Italy;
| | - Francesca Lombardi
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Benedetta Cinque
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Maria Grazia Cifone
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Rodolfo Ippoliti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Elisabetta Benedetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
| | - Annamaria Cimini
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
- Sbarro Institute for Cancer Research and Molecular Medicine, Department of Biology, Temple University, Philadelphia, PA 19122, USA
- Correspondence: (A.C.); (M.d.)
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (V.C.); (M.C.); (M.A.); (F.L.); (B.C.); (M.G.C.); (R.I.); (E.B.)
- Correspondence: (A.C.); (M.d.)
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Turrini E, Sestili P, Fimognari C. Overview of the Anticancer Potential of the "King of Spices" Piper nigrum and Its Main Constituent Piperine. Toxins (Basel) 2020; 12:E747. [PMID: 33256185 PMCID: PMC7761056 DOI: 10.3390/toxins12120747] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 11/18/2020] [Accepted: 11/24/2020] [Indexed: 02/07/2023] Open
Abstract
The main limits of current anticancer therapy are relapses, chemoresistance, and toxic effects resulting from its poor selectivity towards cancer cells that severely impair a patient's quality of life. Therefore, the discovery of new anticancer drugs remains an urgent challenge. Natural products represent an excellent opportunity due to their ability to target heterogenous populations of cancer cells and regulate several key pathways involved in cancer development, and their favorable toxicological profile. Piper nigrum is one of the most popular spices in the world, with growing fame as a source of bioactive molecules with pharmacological properties. The present review aims to provide a comprehensive overview of the anticancer potential of Piper nigrum and its major active constituents-not limited to the well-known piperine-whose undeniable anticancer properties have been reported for different cancer cell lines and animal models. Moreover, the chemosensitizing effects of Piper nigrum in association with traditional anticancer drugs are depicted and its toxicological profile is outlined. Despite the promising results, human studies are missing, which are crucial for supporting the efficacy and safety of Piper nigrum and its single components in cancer patients.
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Affiliation(s)
- Eleonora Turrini
- Department for Life Quality Studies, Alma Mater Studiorum—Università di Bologna, corso d’Augusto 237, 47921 Rimini, Italy;
| | - Piero Sestili
- Department of Biomolecular Sciences (DISB), Università degli Studi di Urbino Carlo Bo, Via I Maggetti 26, 61029 Urbino, Italy;
| | - Carmela Fimognari
- Department for Life Quality Studies, Alma Mater Studiorum—Università di Bologna, corso d’Augusto 237, 47921 Rimini, Italy;
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Abstract
Head and neck cancer is a group of neoplastic diseases affecting the facial, oral, and neck region. It is one of the most common cancers worldwide with an aggressive, invasive evolution. Due to the heterogeneity of the tissues affected, it is particularly challenging to study the molecular mechanisms at the basis of these tumors, and to date we are still lacking accurate targets for prevention and therapy. The Notch signaling is involved in a variety of tumorigenic mechanisms, such as regulation of the tumor microenvironment, aberrant intercellular communication, and altered metabolism. Here, we provide an up-to-date review of the role of Notch in head and neck cancer and draw parallels with other types of solid tumors where the Notch pathway plays a crucial role in emergence, maintenance, and progression of the disease. We therefore give a perspective view on the importance of the pathway in neoplastic development in order to define future lines of research and novel therapeutic approaches.
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Jung Y, Kim JK, Lee E, Cackowski FC, Decker AM, Krebsbach PH, Taichman RS. CXCL12γ induces human prostate and mammary gland development. Prostate 2020; 80:1145-1156. [PMID: 32659025 PMCID: PMC7491592 DOI: 10.1002/pros.24043] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Accepted: 06/11/2020] [Indexed: 01/01/2023]
Abstract
BACKGROUND Epithelial stem cells (ESCs) demonstrate a capacity to maintain normal tissues homeostasis and ESCs with a deregulated behavior can contribute to cancer development. The ability to reprogram normal tissue epithelial cells into prostate or mammary stem-like cells holds great promise to help understand cell of origin and lineage plasticity in prostate and breast cancers in addition to understanding normal gland development. We previously showed that an intracellular chemokine, CXCL12γ induced cancer stem cells and neuroendocrine characteristics in both prostate and breast adenocarcinoma cell lines. However, its role in normal prostate or mammary epithelial cell fate and development remains unknown. Therefore, we sought to elucidate the functional role of CXCL12γ in the regulation of ESCs and tissue development. METHODS Prostate epithelial cells (PNT2) or mammary epithelial cells (MCF10A) with overexpressed CXCL12γ was characterized by quantitative real-time polymerase chain reaction, Western blots, and immunofluorescence for lineage marker expression, and fluorescence activated cell sorting analyses and sphere formation assays to examine stem cell surface phenotype and function. Xenotransplantation animal models were used to evaluate gland or acini formation in vivo. RESULTS Overexpression of CXCL12γ promotes the reprogramming of cells with a differentiated luminal phenotype to a nonluminal phenotype in both prostate (PNT2) and mammary (MCF10A) epithelial cells. The CXCL12γ-mediated nonluminal type cells results in an increase of epithelial stem-like phenotype including the subpopulation of EPCAMLo /CD49fHi /CD24Lo /CD44Hi cells capable of sphere formation. Critically, overexpression of CXCL12γ promotes the generation of robust gland-like structures from both prostate and mammary epithelial cells in in vivo xenograft animal models. CONCLUSIONS CXCL12γ supports the reprogramming of epithelial cells into nonluminal cell-derived stem cells, which facilitates gland development.
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Affiliation(s)
- Younghun Jung
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
- Department of Biologic and Materials Sciences, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
- Co-senior authors
| | - Jin Koo Kim
- Section of Periodontics, University of California Los Angeles School of Dentistry, Los Angeles, CA 90095, USA
| | - Eunsohl Lee
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
| | - Frank C. Cackowski
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA
- Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA
| | - Ann M. Decker
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
| | - Paul H. Krebsbach
- Section of Periodontics, University of California Los Angeles School of Dentistry, Los Angeles, CA 90095, USA
| | - Russell S. Taichman
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA
- Department of Periodontics, University of Alabama at Birmingham, Birmingham, AL 35294, USA
- Co-senior authors
- Corresponding Author Russell S. Taichman D.M.D., D.M.Sc., School of Dentistry, The University of Alabama at Birmingham, 1720 2nd Avenue South, Birmingham, AL 35294-0007, Phone: 205-934-4720,
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27
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Das PK, Zahan T, Abdur Rakib M, Khanam JA, Pillai S, Islam F. Natural Compounds Targeting Cancer Stem Cells: A Promising Resource for Chemotherapy. Anticancer Agents Med Chem 2020; 19:1796-1808. [PMID: 31272363 DOI: 10.2174/1871520619666190704111714] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2019] [Revised: 05/04/2019] [Accepted: 05/20/2019] [Indexed: 12/31/2022]
Abstract
BACKGROUND Cancer Stem Cells (CSCs) are the subpopulation of cancer cells which are directly involved in drug resistance, metastases to distant organ and cancer recurrence. METHODS A systematic literature search was conducted through various electronic databases including, Pubmed, Scopus, Google scholar using the keywords "cancer stem cells" and "natural compounds" in the present study. Articles published between 1999 and 2019 were reviewed. All the expositions concerning CSCs associated cancer pathogenesis and therapy resistance, as well as targeting these properties of CSCs by natural compounds were selected for the current study. RESULTS Natural compounds have always been thought as a rich source of biologically active principles, which target aberrantly activated signaling pathways and other modalities of CSCs, while tethering painful side effects commonly involved in the first-line and second-line chemo-radiotherapies. In this review, we have described the key signaling pathways activated in CSCs to maintain their survival and highlighted how natural compounds interrupt these signaling pathways to minimize therapy resistance, pathogenesis and cancer recurrence properties of CSCs, thereby providing useful strategies to treat cancer or aid in cancer therapy improvement. Like normal stem cells, CSCs rely on different signaling pathways and other properties for their maintenance. Therefore, the success of cancer treatment depends on the development of proper anti-neoplastic drugs capable of intercepting those signaling pathways as well as other properties of CSCs in order to eradicate this evasive subpopulation of cancer cells. CONCLUSION Compounds of natural origin might act as an outstanding source to design novel therapies against cancer stem cells.
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Affiliation(s)
- Plabon K Das
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Tasnim Zahan
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Md Abdur Rakib
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Jahan A Khanam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh
| | - Suja Pillai
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia
| | - Farhadul Islam
- Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi-6205, Bangladesh.,School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Australia
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Eastman AE, Chen X, Hu X, Hartman AA, Pearlman Morales AM, Yang C, Lu J, Kueh HY, Guo S. Resolving Cell Cycle Speed in One Snapshot with a Live-Cell Fluorescent Reporter. Cell Rep 2020; 31:107804. [PMID: 32579930 PMCID: PMC7418154 DOI: 10.1016/j.celrep.2020.107804] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 03/29/2020] [Accepted: 06/02/2020] [Indexed: 12/18/2022] Open
Abstract
Cell proliferation changes concomitantly with fate transitions during reprogramming, differentiation, regeneration, and oncogenesis. Methods to resolve cell cycle length heterogeneity in real time are currently lacking. Here, we describe a genetically encoded fluorescent reporter that captures live-cell cycle speed using a single measurement. This reporter is based on the color-changing fluorescent timer (FT) protein, which emits blue fluorescence when newly synthesized before maturing into a red fluorescent protein. We generated a mouse strain expressing an H2B-FT fusion reporter from a universally active locus and demonstrate that faster cycling cells can be distinguished from slower cycling ones on the basis of the intracellular fluorescence ratio between the FT's blue and red states. Using this reporter, we reveal the native cell cycle speed distributions of fresh hematopoietic cells and demonstrate its utility in analyzing cell proliferation in solid tissues. This system is broadly applicable for dissecting functional heterogeneity associated with cell cycle dynamics in complex tissues.
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Affiliation(s)
- Anna E Eastman
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | - Xinyue Chen
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | - Xiao Hu
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | - Amaleah A Hartman
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA
| | | | - Cindy Yang
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA
| | - Jun Lu
- Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA
| | - Hao Yuan Kueh
- Department of Bioengineering, University of Washington, Seattle, WA 98195, USA
| | - Shangqin Guo
- Department of Cell Biology, Yale University, New Haven, CT 06520, USA; Yale Stem Cell Center, Yale University, New Haven, CT 06520, USA.
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Yuan H, Guo H, Luan X, He M, Li F, Burnett J, Truchan N, Sun D. Albumin Nanoparticle of Paclitaxel (Abraxane) Decreases while Taxol Increases Breast Cancer Stem Cells in Treatment of Triple Negative Breast Cancer. Mol Pharm 2020; 17:2275-2286. [PMID: 32485107 DOI: 10.1021/acs.molpharmaceut.9b01221] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Triple-negative breast cancer (TNBC) has a high rate of metastasis, which is associated with breast cancer stem-like cells (CSCs). Although Taxol (micelle formulation of paclitaxel) is the first line chemotherapy to treat TNBC, it increases CSCs in residual tumors. Abraxane, albumin nanoparticle of paclitaxel, showed lower plasma concentration compared to Taxol in both human and animal models, but it is not clear why Abraxane showed superior efficacy to Taxol in treatment of metastatic breast cancer in humans. In this study, we intend to investigate if Abraxane eliminates CSCs for its better efficacy. The results showed that Abraxane showed similar cytotoxicity in SUM149 cells in comparison with Taxol. Although Abraxane showed 3- to 5-fold lower blood drug concentration compared to Taxol, it achieved similar tumor drug concentration and 10-fold higher tumor/plasma ratio in SUM149 xenograft NOD/SCID mouse model. In addition, Abraxane and Taxol showed similar efficacy to shrink the tumor size in orthotopic breast cancer NOD/SCID mouse model. However, Abraxane decreased breast CSCs frequency by 3- to 9-fold, while Taxol increased breast CSCs frequency in an orthotopic breast cancer NOD/SCID mouse model. Furthermore, Abraxane increased 3- to 15-fold intracellular uptake in both ALDH+ CSCs and differentiated ALDH- cells in comparison with Taxol, which provides a mechanism for Abraxane's superior efficacy to eliminate CSCs in comparison with Taxol. Our data suggest albumin nanoparticle Abraxane may have a broad implication to enhance drug's efficacy by eliminating breast cancer stem cells for treatment of metastatic diseases.
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Affiliation(s)
- Hebao Yuan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Hongwei Guo
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Xin Luan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Miao He
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Feng Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Joseph Burnett
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Nathan Truchan
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
| | - Duxin Sun
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, North Campus Research Complex, Building 520, 1600 Huron Parkway, Ann Arbor, Michigan 48109, United States
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Ganesan K, Jayachandran M, Xu B. Diet-Derived Phytochemicals Targeting Colon Cancer Stem Cells and Microbiota in Colorectal Cancer. Int J Mol Sci 2020; 21:E3976. [PMID: 32492917 PMCID: PMC7312951 DOI: 10.3390/ijms21113976] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/28/2020] [Accepted: 05/30/2020] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a fatal disease caused by the uncontrolled propagation and endurance of atypical colon cells. A person's lifestyle and eating pattern have significant impacts on the CRC in a positive and/or negative way. Diet-derived phytochemicals modulate the microbiome as well as targeting colon cancer stem cells (CSCs) that are found to offer significant protective effects against CRC, which were organized in an appropriate spot on the paper. All information on dietary phytochemicals, gut microbiome, CSCs, and their influence on CRC were accessed from the various databases and electronic search engines. The effectiveness of CRC can be reduced using various dietary phytochemicals or modulating microbiome that reduces or inverses the progression of a tumor as well as CSCs, which could be a promising and efficient way to reduce the burden of CRC. Phytochemicals with modulation of gut microbiome continue to be auspicious investigations in CRC through noticeable anti-tumorigenic effects and goals to CSCs, which provides new openings for cancer inhibition and treatment.
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Affiliation(s)
- Kumar Ganesan
- Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China; (K.G.); (M.J.)
- Laboratory and Clinical Research Institute for Pain, Department of Anesthesiology, The University of Hong Kong, Hong Kong SAR, China
| | - Muthukumaran Jayachandran
- Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China; (K.G.); (M.J.)
| | - Baojun Xu
- Food Science and Technology Programme, Beijing Normal University-Hong Kong Baptist University United International College, Zhuhai 519087, China; (K.G.); (M.J.)
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Kuran D, Pogorzelska A, Wiktorska K. Breast Cancer Prevention-Is there a Future for Sulforaphane and Its Analogs? Nutrients 2020; 12:nu12061559. [PMID: 32471217 PMCID: PMC7352481 DOI: 10.3390/nu12061559] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/20/2020] [Accepted: 05/22/2020] [Indexed: 12/30/2022] Open
Abstract
Breast cancer is the most prevalent type of cancer among women worldwide. There are several recommended methods of breast cancer prevention, including chemoprevention. There are several approved drugs used to prevent breast cancer occurrence or recurrence and metastasizing. There are also a number of new substances undergoing clinical trials and at the stage of initial study. Studies suggest that dietary factors play a crucial role in breast cancer etiology. Epidemiological studies indicate that in particular vegetables from the Brassicaceae family are a rich source of chemopreventive substances, with sulforaphane (SFN) being one of the most widely studied and characterized. This review discusses potential applicability of SFN in breast cancer chemoprevention. A comprehensive review of the literature on the impact of SFN on molecular signalling pathways in breast cancer and breast untransformed cells is presented. The presented results of in vitro and in vivo studies show that this molecule has a potential to act as a preventive molecule either to prevent disease development or recurrence and metastasizing, and as a compound protecting normal cells against the toxic effects of cytostatics. Finally, the still scanty attempts to develop an improved analog are also presented and discussed.
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Affiliation(s)
- Dominika Kuran
- Department of Pharmacology, National Medicines Institute, 00-725 Warsaw, Poland;
| | - Anna Pogorzelska
- Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 00-725 Warsaw, Poland;
| | - Katarzyna Wiktorska
- Department of Drug Biotechnology and Bioinformatics, National Medicines Institute, 00-725 Warsaw, Poland;
- OncoBoost Ltd., 02-089 Warsaw, Poland
- Correspondence:
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A STAT3 of Addiction: Adipose Tissue, Adipocytokine Signalling and STAT3 as Mediators of Metabolic Remodelling in the Tumour Microenvironment. Cells 2020; 9:cells9041043. [PMID: 32331320 PMCID: PMC7226520 DOI: 10.3390/cells9041043] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/15/2020] [Accepted: 04/17/2020] [Indexed: 12/12/2022] Open
Abstract
Metabolic remodelling of the tumour microenvironment is a major mechanism by which cancer cells survive and resist treatment. The pro-oncogenic inflammatory cascade released by adipose tissue promotes oncogenic transformation, proliferation, angiogenesis, metastasis and evasion of apoptosis. STAT3 has emerged as an important mediator of metabolic remodelling. As a downstream effector of adipocytokines and cytokines, its canonical and non-canonical activities affect mitochondrial functioning and cancer metabolism. In this review, we examine the central role played by the crosstalk between the transcriptional and mitochondrial roles of STAT3 to promote survival and further oncogenesis within the tumour microenvironment with a particular focus on adipose-breast cancer interactions.
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Zhou L, Wang D, Sheng D, Xu J, Chen W, Qin Y, Du R, Yang X, He X, Xie N, Liu S, Zhang L. NOTCH4 maintains quiescent mesenchymal-like breast cancer stem cells via transcriptionally activating SLUG and GAS1 in triple-negative breast cancer. Theranostics 2020; 10:2405-2421. [PMID: 32104513 PMCID: PMC7019177 DOI: 10.7150/thno.38875] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Accepted: 12/21/2019] [Indexed: 12/18/2022] Open
Abstract
Rationale: NOTCH4 receptor has been implicated in triple-negative breast cancer (TNBC) development and breast cancer stem cell (BCSC) regulation. However, the potential of NOTCH4 as a BCSC marker and the underlying mechanisms remain unclear. Methods: In this study, we determined the expression and activation of NOTCH4 in breast cancer cell lines and tumor samples by qRT-PCR, western blotting and immunohistochemistry. Subsequently, in vitro and in vivo serial dilution experiments were performed to demonstrate the application of NOTCH4 as an efficient mesenchymal-like (ML)-BCSC marker in TNBC. Stable overexpression of activated NOTCH4 and knockdown cell lines were established using lentivirus. RNA-seq and qRT-PCR were employed to reveal the downstream effectors of NOTCH4, followed by dual-luciferase reporter and chromatin immunoprecipitation assays to identify the genuine binding sites of NOTCH4 on SLUG and GAS1 promoters. Transwell assay, mammosphere formation and chemoresistance experiments were performed to determine the effects of SLUG, GAS1 and NOTCH4 on the mesenchymal-like characteristics of TNBC cells. Survival analysis was used to study the relation of NOTCH4, SLUG and GAS1 with prognosis of breast cancer. Results: NOTCH4 is aberrantly highly expressed and activated in TNBC, which contributes to the maintenance of ML-BCSCs. Furthermore, NOTCH4 shows significantly higher efficiency in labeling ML-BCSCs than the currently commonly used CD24-CD44+ marker. Mechanistically, NOTCH4 transcriptionally upregulates SLUG and GAS1 to promote EMT and quiescence in TNBC, respectively. The effects of NOTCH4 can be mimicked by simultaneous overexpression of SLUG and GAS1. Moreover, SLUG is also involved in harnessing GAS1, a known tumor suppressor gene, via its anti-apoptotic function. Conclusions: Our findings reveal that the NOTCH4-SLUG-GAS1 circuit serves as a potential target for tumor intervention by overcoming stemness of ML-BCSCs and by conquering the lethal chemoresistance and metastasis of TNBC.
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Amino Acid-Mediated Metabolism: A New Power to Influence Properties of Stem Cells. Stem Cells Int 2019; 2019:6919463. [PMID: 31885621 PMCID: PMC6915148 DOI: 10.1155/2019/6919463] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 11/05/2019] [Accepted: 11/15/2019] [Indexed: 01/10/2023] Open
Abstract
The self-renewal and differentiation potentials of stem cells are dependent on amino acid (AA) metabolism. We review the literature on the metabolic preference of both cancer and noncancer stem cells. The balance in AA metabolism is responsible for maintaining the functionality of noncancer stem cells, and altering the levels of AAs can influence the malignant biological behavior of cancer stem cells. AAs are considered nutrients participating in metabolism and playing a critical role in maintaining the activity of normal stem cells and the effect of therapy of cancer stem cells. Targeting AA metabolism helps inhibit the stemness of cancer stem cells and remodels the function of normal stem cells. This review summarizes the metabolic characteristics and regulation pathways of AA in different stem cells, not only from the nutritional perspective but also from the genomic perspective that have been reported in the recent five years. In addition, we briefly survey new therapeutic modalities that may help eradicate cancer stem cells by exploiting nutrient deprivation. Understanding AA uptake characteristics helps researchers define the preference for AA in different stem cells and enables clinicians make timely interventions to specifically target the cell behavior.
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Yi Qi Jie Du Decoction Inhibits Proliferation and Induces Apoptosis of Nasopharyngeal Carcinoma Stem Cells Through Mitochondrial Apoptosis Pathway. DIGITAL CHINESE MEDICINE 2019. [DOI: 10.1016/j.dcmed.2020.01.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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Xu Y, Chen C, Hellwarth PB, Bao X. Biomaterials for stem cell engineering and biomanufacturing. Bioact Mater 2019; 4:366-379. [PMID: 31872161 PMCID: PMC6909203 DOI: 10.1016/j.bioactmat.2019.11.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 11/09/2019] [Accepted: 11/20/2019] [Indexed: 12/15/2022] Open
Abstract
Recent years have witnessed the expansion of tissue failures and diseases. The uprising of regenerative medicine converges the sight onto stem cell-biomaterial based therapy. Tissue engineering and regenerative medicine proposes the strategy of constructing spatially, mechanically, chemically and biologically designed biomaterials for stem cells to grow and differentiate. Therefore, this paper summarized the basic properties of embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and adult stem cells. The properties of frequently used biomaterials were also described in terms of natural and synthetic origins. Particularly, the combination of stem cells and biomaterials for tissue repair applications was reviewed in terms of nervous, cardiovascular, pancreatic, hematopoietic and musculoskeletal system. Finally, stem-cell-related biomanufacturing was envisioned and the novel biofabrication technologies were discussed, enlightening a promising route for the future advancement of large-scale stem cell-biomaterial based therapeutic manufacturing.
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Affiliation(s)
| | | | | | - Xiaoping Bao
- Davidson School of Chemical Engineering, Purdue University, West Lafayette, West Lafayette, IN, 47907, USA
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Pacheco CMR, Ferreira PE, Saçaki CS, Tannous LA, Zotarelli-Filho IJ, Guarita-Souza LC, de Carvalho KAT. In vitro differentiation capacity of human breastmilk stem cells: A systematic review. World J Stem Cells 2019; 11:1005-1019. [PMID: 31768226 PMCID: PMC6851011 DOI: 10.4252/wjsc.v11.i11.1005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/17/2019] [Accepted: 09/04/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Mesenchymal stem cells are pluripotent cells that have the ability to generate cells from a cell line or in other cell types from different tissues but from the same origin. Although those cells have more limited differentiation capacity than embryonic stem cells, they are easily obtained from somatic tissue and can be grown in large quantities. This characteristic of undifferentiated stem cells differentiating into different cell lines arouses strategies in regenerative medicine for the treatment of different diseases such as neurodegenerative diseases.
AIM To evaluate the cell differentiation capacity of human breastmilk stem cells for the three germ layers by a systematic review.
METHODS The searched databases were PubMed, EMBASE, OVID, and COCHRANE LIBRARY, published between 2007 and 2018 in the English language. All were in vitro studies for analysis of the "cell differentiation potential" in the literature using the keywords “human breastmilk,” “stem cells,” and keywords combined with the Boolean operator “NOT” were used to exclude those articles that had the word “CANCER” and their respective synonyms, which were previously consulted according to medical subject heading terms. PRISMA 2009 guidelines were followed in this study.
RESULTS A total of 315 titles and abstracts of articles were examined. From these, 21 were in common with more than one database, leaving 294 articles for analysis. Of that total, five publications met the inclusion criteria. When analyzing the publications, it was demonstrated that human breastmilk stem cells have a high cellular plasticity, exhibiting the ability to generate cells of all three germ layers, endoderm, mesoderm, and ectoderm, demonstrating their stemness. Those cells expressed the genes, TRA-1-60/81, octamer-binding transcription factor 4, and NANOG, of which NANOG, a critical regulator for self-renewal and maintenance, was the most highly expressed. Those cells have the ability to differentiate in vitro into adipocytes, chondrocytes, osteocytes, oligodendrocytes, astrocytes, and neurons as well hepatocytes, β-pancreatic cells, and cardiomyocytes.
CONCLUSION Although the literature has been scarce, the pluripotentiality of these cells represents great potential for tissue engineering and cellular therapy. Further studies for safe clinical translation are needed.
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Affiliation(s)
- Camila Maria Ribeiro Pacheco
- Cell Therapy and Biotechnology in Regenerative Medicine Department, Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculty, Curitiba 80.240-020, Paraná, Brazil
| | - Priscila Elias Ferreira
- Cell Therapy and Biotechnology in Regenerative Medicine Department, Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculty, Curitiba 80.240-020, Paraná, Brazil
| | - Claudia Sayuri Saçaki
- Cell Therapy and Biotechnology in Regenerative Medicine Department, Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculty, Curitiba 80.240-020, Paraná, Brazil
| | - Luana Alves Tannous
- PUCPR-Institute of Biological and Health Sciences, CCBS, Curitiba 80.215-901, Paraná, Brazil
| | - Idiberto José Zotarelli-Filho
- Post Graduate and Continuing Education (Unipos), Department of Scientific Production, São José do Rio Preto 15.020-040, São Paulo, Brazil
| | | | - Katherine Athayde Teixeira de Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Department, Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research and Pequeno Príncipe Faculty, Curitiba 80.240-020, Paraná, Brazil
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Aljarrah K, Al-Akhras MA, Al-Khalili DJ, Ababneh Z. The feasibility of using Saffron to reduce the photosensitivity reaction of selected photosensitizers using red blood cells and staphylococcusAureus bacteria as targets. Photodiagnosis Photodyn Ther 2019; 29:101590. [PMID: 31689512 DOI: 10.1016/j.pdpdt.2019.101590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 10/21/2019] [Accepted: 10/28/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND The photosensitivity reaction which appears after a Photodynamic therapy treatment session is a challenge that needs further investigation. The goal of this research is to evaluate the possibility of using saffron to reduce or control this photosensitivity reaction and to present mathematical modeling of the cell survival curves and their dependency on saffron concentration. METHODS Red blood cells (RBC) and Staphylococcus aureus Bacteria (STB) were used as targets in this study. The Photosensitivity of Rose Bengali, Methylene Blue, and Photofrin independently and incorporated with saffron was investigated for continued irradiation at different Saffron concentrations. Gompertz's function was used to fit the survival curve parameters. The 50% cell survival rate was fit to an empirical formula based on Saffron concentrations. RESULTS Saffron inhibits the photosensitivity reaction of the three photosensitizers and causes a significant increase in the 50% survival rate time (t50) for RBC`s and STB. Saffron didn't show phototoxicity when incubated alone with RBC`s and STB. The survival curve parameters of the RBCs and STB showed a good fit to the Gompertz function. Saffron concentration is related to the RBC`s t50 based on power dependency of 0.56, 0.38 and 0.31 for Photofrin, Methylene Blue and Rose Bengali respectively and 0.1 on STB for Rose Bengali. CONCLUSION Saffron can efficiently be used to reduce the photosensitivity reaction of Photosensitizers after a PDT treatment session. Gompertz function was found to be an appropriate mathematical model for survival rate curves. The t50 and the saffron concentration are well related through a power dependence empirical formula.
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Affiliation(s)
- Khaled Aljarrah
- Bio-Medical Physics Laboratory, Department of Physics, Jordan University of Science & Technology (JUST), P.O. Box 3030, Irbid 22110, Jordan.
| | - M-Ali Al-Akhras
- Bio-Medical Physics Laboratory, Department of Physics, Jordan University of Science & Technology (JUST), P.O. Box 3030, Irbid 22110, Jordan
| | | | - Zaid Ababneh
- Physics Department, Yarmouk University, Irbid 211-63, Jordan
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Hass R, von der Ohe J, Ungefroren H. Potential Role of MSC/Cancer Cell Fusion and EMT for Breast Cancer Stem Cell Formation. Cancers (Basel) 2019; 11:1432. [PMID: 31557960 PMCID: PMC6826868 DOI: 10.3390/cancers11101432] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/20/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023] Open
Abstract
Solid tumors comprise of maturated cancer cells and self-renewing cancer stem-like cells (CSCs), which are associated with various other nontumorigenic cell populations in the tumor microenvironment. In addition to immune cells, endothelial cells, fibroblasts, and further cell types, mesenchymal stroma/stem-like cells (MSC) represent an important cell population recruited to tumor sites and predominantly interacting with the different cancer cells. Breast cancer models were among the first to reveal distinct properties of CSCs, however, the cellular process(es) through which these cells are generated, maintained, and expanded within neoplastic tissues remains incompletely understood. Here, we discuss several possible scenarios that are not mutually exclusive but may even act synergistically: fusion of cancer cells with MSC to yield hybrid cells and/or the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells by MSC, which can relay signals for retrodifferentiation and eventually, the generation of breast CSCs (BCSCs). In either case, the consequences may be promotion of self-renewal capacity, tumor cell plasticity and heterogeneity, an increase in the cancer cells' invasive and metastatic potential, and the acquisition of resistance mechanisms towards chemo- or radiotherapy. While specific signaling mechanisms involved in each of these properties remain to be elucidated, the present review article focusses on a potential involvement of cancer cell fusion and EMT in the development of breast cancer stem cells.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany.
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
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Hill EM, Esper RM, Sen A, Simon BR, Aslam MN, Jiang Y, Dame MK, McClintock SD, Colacino JA, Djuric Z, Wicha MS, Smith WL, Brenner DE. Dietary polyunsaturated fatty acids modulate adipose secretome and is associated with changes in mammary epithelial stem cell self-renewal. J Nutr Biochem 2019; 71:45-53. [PMID: 31272031 PMCID: PMC6917480 DOI: 10.1016/j.jnutbio.2019.05.007] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/07/2023]
Abstract
Chronic low-grade adipose inflammation, characterized by aberrant adipokine production and pro-inflammatory macrophage activation/polarization is associated with increased risk of breast cancer. Adipocyte fatty acid composition is influenced by dietary availability and may regulate adipokine secretion and adipose inflammation. After feeding F344 rats for 20 weeks with a Western diet or a fish oil-supplemented diet, we cultured primary rat adipose tissue in a three-dimensional explant culture and collected the conditioned medium. The rat adipose tissue secretome was assayed using the Proteome Profiler Cytokine XL Array, and adipose tissue macrophage polarization (M1/M2 ratio) was assessed using the iNOS/ARG1 ratio. We then assessed the adipokine's effects upon stem cell self-renewal using primary human mammospheres from normal breast mammoplasty tissue. Adipose from rats fed the fish oil diet had an ω-3:ω-6 fatty acid ratio of 0.28 compared to 0.04 in Western diet rats. The adipokine profile from the fish oil-fed rats was shifted toward adipokines associated with reduced inflammation compared to the rats fed the Western diet. The M1/M2 macrophage ratio decreased by 50% in adipose of fish oil-fed rats compared to that from rats fed the Western diet. Conditioned media from rats fed the high ω-6 Western diet increased stem cell self-renewal by 62%±9% (X¯%±SD) above baseline compared to only an 11%±11% increase with the fish oil rat adipose. Modulating the adipokine secretome with dietary interventions therefore may alter stromal-epithelial signaling that plays a role in controlling mammary stem cell self-renewal.
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Affiliation(s)
- Evan M Hill
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Raymond M Esper
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Ananda Sen
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Becky R Simon
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Muhammad N Aslam
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Yan Jiang
- MD Anderson Cancer Center, Houston, TX, USA
| | - Michael K Dame
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Shannon D McClintock
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Justin A Colacino
- Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Zora Djuric
- Department of Family Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, MI, USA
| | - Max S Wicha
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - William L Smith
- Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Dean E Brenner
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
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Herheliuk T, Perepelytsina O, Ugnivenko A, Ostapchenko L, Sydorenko M. Investigation of multicellular tumor spheroids enriched for a cancer stem cell phenotype. Stem Cell Investig 2019; 6:21. [PMID: 31559308 DOI: 10.21037/sci.2019.06.07] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Accepted: 06/12/2019] [Indexed: 12/12/2022]
Abstract
Background Cancer stem cells (CSCs) provide self-renewal of the tumor after radiation and chemotherapy. These cells are important during tumor development. The in vitro model of avascular tumor that enriched of cells with stem like characteristics is critical to understanding of the role CSCs in the tumor. Methods Cell viability was evaluated by MTT assay. The expression of cancer stem cells markers (CD133, CD44, CD24 and bmi-1) in 2D cell culture and multicellular tumor spheroids (MCTS) of MCF-7 cells was evaluated. The Stemi2000 software AxioVisionRed 4.7 was used for image processing. The volume of spheroids was calculated by Bjerkvig formula. Results The highest expression of CD133, CD44, CD24 and bmi-1 receptors was detected in MCTS, enriched with cancer stem cells (eMCTS). Cell aggregates of eMCTS culture were returned from suspension to adhesive conditions. It was found that the cells of the MCTS surface layers were enriched with CD133, CD44, CD24, bmi-1, EpCAM, vim markers, but not adherent cells. eMCTS are less sensitive to anticancer drugs (cisplatin, methotrexate and doxorubicin), than adhesive cell culture and MCTS cultured under standard conditions in a complete nutrient medium (P<0.05). Conclusions We observed that eMCTS population possesses aggressive phenotypic characteristics such as invasion, cancer stem cell markers and chemoresistance. eMCTS model could improve the screening efficiency of therapeutical agents against CSCs.
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Affiliation(s)
- Tetiana Herheliuk
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine.,Educational and Scientific Centre "Institute of Biology & Medicine", 03187, Kyiv, Ukraine
| | - Olena Perepelytsina
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine
| | - Andriy Ugnivenko
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine
| | - Lyudmila Ostapchenko
- Educational and Scientific Centre "Institute of Biology & Medicine", 03187, Kyiv, Ukraine
| | - Mykhailo Sydorenko
- Department of Biotechnical Problems of Diagnostics, Institute for Problems of Cryobiology and Cryomedicine, National Academy of Science of Ukraine, 03028, Kyiv, Ukraine
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Roberts CM, Cardenas C, Tedja R. The Role of Intra-Tumoral Heterogeneity and Its Clinical Relevance in Epithelial Ovarian Cancer Recurrence and Metastasis. Cancers (Basel) 2019; 11:E1083. [PMID: 31366178 PMCID: PMC6721439 DOI: 10.3390/cancers11081083] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/22/2019] [Accepted: 07/27/2019] [Indexed: 12/14/2022] Open
Abstract
Epithelial ovarian cancer is the deadliest gynecologic cancer, due in large part to recurrent tumors. Recurrences tend to have metastasized, mainly in the peritoneal cavity and developed resistance to the first line chemotherapy. Key to the progression and ultimate lethality of ovarian cancer is the existence of extensive intra-tumoral heterogeneity (ITH). In this review, we describe the genetic and epigenetic changes that have been reported to give rise to different cell populations in ovarian cancer. We also describe at length the contributions made to heterogeneity by both linear and parallel models of clonal evolution and the existence of cancer stem cells. We dissect the key biological signals from the tumor microenvironment, both directly from other cell types in the vicinity and soluble or circulating factors. Finally, we discuss the impact of tumor heterogeneity on the choice of therapeutic approaches in the clinic. Variability in ovarian tumors remains a major barrier to effective therapy, but by leveraging future research into tumor heterogeneity, we may be able to overcome this barrier and provide more effective, personalized therapy to patients.
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Affiliation(s)
- Cai M Roberts
- Obstetrics, Gynecology and Reproductive Sciences Department, Yale School of Medicine, New Haven, CT 06520, USA
| | - Carlos Cardenas
- Obstetrics, Gynecology and Reproductive Sciences Department, Yale School of Medicine, New Haven, CT 06520, USA
| | - Roslyn Tedja
- Obstetrics, Gynecology and Reproductive Sciences Department, Yale School of Medicine, New Haven, CT 06520, USA.
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Pellacani D, Tan S, Lefort S, Eaves CJ. Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer. EMBO J 2019; 38:e100330. [PMID: 31304632 PMCID: PMC6627240 DOI: 10.15252/embj.2018100330] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Revised: 10/22/2018] [Accepted: 11/08/2018] [Indexed: 12/18/2022] Open
Abstract
The mammary gland in adult women consists of biologically distinct cell types that differ in their surface phenotypes. Isolation and molecular characterization of these subpopulations of mammary cells have provided extensive insights into their different transcriptional programs and regulation. This information is now serving as a baseline for interpreting the heterogeneous features of human breast cancers. Examination of breast cancer mutational profiles further indicates that most have undergone a complex evolutionary process even before being detected. The consequent intra-tumoral as well as inter-tumoral heterogeneity of these cancers thus poses major challenges to deriving information from early and hence likely pervasive changes in potential therapeutic interest. Recently described reproducible and efficient methods for generating human breast cancers de novo in immunodeficient mice transplanted with genetically altered primary cells now offer a promising alternative to investigate initial stages of human breast cancer development. In this review, we summarize current knowledge about key transcriptional regulatory processes operative in these partially characterized subpopulations of normal human mammary cells and effects of disrupting these processes in experimentally produced human breast cancers.
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Affiliation(s)
- Davide Pellacani
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
| | - Susanna Tan
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
| | - Sylvain Lefort
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
| | - Connie J Eaves
- Terry Fox LaboratoryBritish Columbia Cancer AgencyVancouverBCCanada
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Piperine: role in prevention and progression of cancer. Mol Biol Rep 2019; 46:5617-5629. [PMID: 31273611 DOI: 10.1007/s11033-019-04927-z] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 06/15/2019] [Indexed: 12/18/2022]
Abstract
Cancer is among the leading causes of death worldwide. Several pharmacological protocols have been developed in order to block tumor progression often showing partial efficacy and severe counterproductive effects. It is now conceived that a healthy lifestyle coupled with the consumption of certain phytochemicals can play a protective role against tumor development and progression. According to this vision, it has been introduced the concept of "chemoprevention". This term refers to natural agents with the capability to interfere with the tumorigenesis and metastasis, or at least, attenuate the cancer-related symptoms. Piperine (1-Piperoylpiperidine), a main extract of Piper longum and Piper nigrum, is an alkaloid with a long history of medicinal use. In fact, it exhibits a variety of biochemical and pharmaceutical properties, including chemopreventive activities without significant cytotoxic effects on normal cells, at least at doses < of 250 µg/ml. The aim of this review is to discuss the relevant molecular and cellular mechanisms underlying the chemopreventive action of this natural alkaloid.
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Wang MY, Qiu YH, Cai ML, Zhang CH, Wang XW, Liu H, Chen Y, Zhao WL, Liu JB, Shao RG. Role and molecular mechanism of stem cells in colorectal cancer initiation. J Drug Target 2019; 28:1-10. [PMID: 31244351 DOI: 10.1080/1061186x.2019.1632317] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In recent years, the rate of colorectal cancer has sharply increased, especially in China, where it ranks second for the number of cancer fatalities. Currently, the treatment of colorectal cancer patients involves the combination of resection surgery and treatment with postoperative anticancer drugs such as 5-FU and oxaliplatin. However, recurrence and metastasis after treatment are still the dominant reasons for the low survival rate. Colorectal cancer stem cells (CSCs) are regarded as the key contributors to tumour recurrence and metastasis due to their resistance to chemotherapy drugs and their extremely high tumourigenicity. Once CSCs overcome chemotherapy treatment, they continue to survive and reinitiate proliferation to form tumours, leading to recurrence. The dominant reason for CSC resistance is that most anticancer drugs are aimed at inhibiting proliferative pathways in cancer cells that differ from those in CSCs. Therefore, studies on the characteristics of CSCs and their intracellular molecular pathways are essential for the exploration of CSC-targeted drugs. In this report, we review recent advances in the research of CSCs and, in particular, review the important intracellular molecular pathways, such as HOXA5-catenin, STRAP-NOTCH and YAP/TAZ, related to the maintenance and differentiation of stem cells to generate a theoretical basis for the exploration of CSC-targeted drugs.
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Affiliation(s)
- Meng-Yan Wang
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yu-Han Qiu
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Mei-Lian Cai
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Cong-Hui Zhang
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiao-Wei Wang
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Hong Liu
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yi- Chen
- College of Pharmaceutical Sciences & Chinese Medicine, Southwest University, Chongqing, China
| | - Wu-Li Zhao
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jing-Bo Liu
- Department of Urology, Dongzhimen Hospital Beijing University of Chinese Medicine, Beijing, People's Republic of China
| | - Rong-Guang Shao
- Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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46
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Giudice A, Barbieri A, Bimonte S, Cascella M, Cuomo A, Crispo A, D'Arena G, Galdiero M, Della Pepa ME, Botti G, Caraglia M, Capunzo M, Arra C, Montella M. Dissecting the prevention of estrogen-dependent breast carcinogenesis through Nrf2-dependent and independent mechanisms. Onco Targets Ther 2019; 12:4937-4953. [PMID: 31388303 PMCID: PMC6607693 DOI: 10.2147/ott.s183192] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/14/2018] [Indexed: 12/19/2022] Open
Abstract
Breast cancer is the most common malignancy among women worldwide. Various studies indicate that prolonged exposure to elevated levels of estrogens is associated with development of breast cancer. Both estrogen receptor-dependent and independent mechanisms can contribute to the carcinogenic effects of estrogens. Among them, the oxidative metabolism of estrogens plays a key role in the initiation of estradiol-induced breast cancer by generation of reactive estrogen quinones as well as the associated formation of oxygen free radicals. These genotoxic metabolites can react with DNA to form unstable DNA adducts which generate mutations leading to the initiation of breast cancer. A variety of endogenous and exogenous factors can alter estrogen homeostasis and generate genotoxic metabolites. The use of specific phytochemicals and dietary supplements can inhibit the risk of breast cancer not only by the modulation of several estrogen-activating enzymes (CYP19, CYP1B1) but also through the induction of various cytoprotective enzymes (eg, SOD3, NQO1, glutathione S-transferases, OGG-1, catechol-O-methyltransferases, CYP1B1A, etc.) that reestablish the homeostatic balance of estrogen metabolism via nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent and independent mechanisms.
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Affiliation(s)
- Aldo Giudice
- Epidemiology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Antonio Barbieri
- S.S.D Sperimentazione Animale, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Sabrina Bimonte
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Marco Cascella
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Arturo Cuomo
- Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Anna Crispo
- Epidemiology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Giovanni D'Arena
- Hematology and Stem Cell Transplantation Unit, IRCCS Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy
| | - Massimiliano Galdiero
- Department of Experimental Medicine, Università della Campania “Luigi Vanvitelli”, 80134Naples, Italy
| | - Maria Elena Della Pepa
- Department of Experimental Medicine, Università della Campania “Luigi Vanvitelli”, 80134Naples, Italy
| | - Gerardo Botti
- Scientific Direction, Istituto Nazionale Tumori-IRCCS “Fondazione G. Pascale”, Naples, Italy
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, University of Campania “Luigi Vanvitelli”, 80138Naples, Italy
| | - Mario Capunzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, Baronissi, 84081Salerno, Italy
| | - Claudio Arra
- S.S.D Sperimentazione Animale, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
| | - Maurizio Montella
- Epidemiology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale”, IRCCS, Naples, Italy
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47
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Fitzpatrick C, Bendek MF, Briones M, Farfán N, Silva VA, Nardocci G, Montecino M, Boland A, Deleuze JF, Villegas J, Villota C, Silva V, Lobos-Gonzalez L, Borgna V, Barrey E, Burzio LO, Burzio VA. Mitochondrial ncRNA targeting induces cell cycle arrest and tumor growth inhibition of MDA-MB-231 breast cancer cells through reduction of key cell cycle progression factors. Cell Death Dis 2019; 10:423. [PMID: 31142736 PMCID: PMC6541642 DOI: 10.1038/s41419-019-1649-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 04/05/2019] [Accepted: 04/29/2019] [Indexed: 12/24/2022]
Abstract
The family of long noncoding mitochondrial RNAs (ncmtRNAs), comprising sense (SncmtRNA), and antisense (ASncmtRNA-1 and ASncmtRNA-2) members, are differentially expressed according to cell proliferative status; SncmtRNA is expressed in all proliferating cells, while ASncmtRNAs are expressed in normal proliferating cells, but is downregulated in tumor cells. ASncmtRNA knockdown with an antisense oligonucleotide induces massive apoptosis in tumor cell lines, without affecting healthy cells. Apoptotic death is preceded by proliferation blockage, suggesting that these transcripts are involved in cell cycle regulation. Here, we show that ASncmtRNA knockdown induces cell death preceded by proliferative blockage in three different human breast cancer cell lines. This effect is mediated by downregulation of the key cell cycle progression factors cyclin B1, cyclin D1, CDK1, CDK4, and survivin, the latter also constituting an essential inhibitor of apoptosis, underlying additionally the onset of apoptosis. The treatment also induces an increase in the microRNA hsa-miR-4485-3p, whose sequence maps to ASncmtRNA-2 and transfection of MDA-MB-231 cells with a mimic of this miRNA induces cyclin B1 and D1 downregulation. Other miRNAs that are upregulated include nuclear-encoded hsa-miR-5096 and hsa-miR-3609, whose mimics downregulate CDK1. Our results suggest that ASncmtRNA targeting blocks tumor cell proliferation through reduction of essential cell cycle proteins, mediated by mitochondrial and nuclear miRNAs. This work adds to the elucidation of the molecular mechanisms behind cell cycle arrest preceding tumor cell apoptosis induced by ASncmtRNA knockdown. As proof-of-concept, we show that in vivo knockdown of ASncmtRNAs results in drastic inhibition of tumor growth in a xenograft model of MDA-MB-231 subcutaneous tumors, further supporting this approach for the development of new therapeutic strategies against breast cancer.
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Affiliation(s)
- Christopher Fitzpatrick
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Department of Biological Sciences, Faculty of Life Sciences, Universidad Andrés Bello, 8370134, Santiago, Chile
| | - Maximiliano F Bendek
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Department of Biological Sciences, Faculty of Life Sciences, Universidad Andrés Bello, 8370134, Santiago, Chile
| | - Macarena Briones
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile
| | - Nicole Farfán
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Department of Biological Sciences, Faculty of Life Sciences, Universidad Andrés Bello, 8370134, Santiago, Chile
| | - Valeria A Silva
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Valparaíso Interdisciplinary Neuroscience Center, Faculty of Sciences, Universidad de Valparaíso, Valparaíso, 2360102, Chile
| | - Gino Nardocci
- Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Life Sciences and Faculty of Medicine, Universidad Andrés Bello, 8370134, Santiago, Chile
| | - Martín Montecino
- Center for Biomedical Research and FONDAP Center for Genome Regulation, Faculty of Life Sciences and Faculty of Medicine, Universidad Andrés Bello, 8370134, Santiago, Chile
| | - Anne Boland
- Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Evry, France
| | - Jean-François Deleuze
- Centre National de Recherche en Génomique Humaine (CNRGH), Institut de Biologie François Jacob, CEA, Evry, France
| | - Jaime Villegas
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Department of Biological Sciences, Faculty of Life Sciences, Universidad Andrés Bello, 8370134, Santiago, Chile.,Andes Biotechnologies Global Inc., Burlingame, CA, USA.,Center for Veterinary Medicine, Faculty of Life Sciences, Universidad Andrés Bello, Santiago, Chile
| | - Claudio Villota
- School of Nutrition and Diet, Faculty of Health, Universidad Bernardo O'Higgins, Santiago, Chile
| | - Verónica Silva
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile
| | - Lorena Lobos-Gonzalez
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Center for Regenerative Medicine, Faculty of Medicine, Clínica Alemana & Universidad del Desarrollo, Santiago, Chile
| | - Vincenzo Borgna
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Faculty of Medical Sciences, Universidad de Santiago de Chile, Santiago, Chile
| | - Eric Barrey
- INRA, Génétique Animale et Biologie Intégrative UMR1313, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France
| | - Luis O Burzio
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile.,Department of Biological Sciences, Faculty of Life Sciences, Universidad Andrés Bello, 8370134, Santiago, Chile.,Andes Biotechnologies Global Inc., Burlingame, CA, USA
| | - Verónica A Burzio
- Fundación Ciencia & Vida/Andes Biotechnologies SpA, 7780272, Santiago, Chile. .,Department of Biological Sciences, Faculty of Life Sciences, Universidad Andrés Bello, 8370134, Santiago, Chile. .,Andes Biotechnologies Global Inc., Burlingame, CA, USA.
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48
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Wen SY, Chen YY, Deng CM, Zhang CQ, Jiang MM. Nerigoside suppresses colorectal cancer cell growth and metastatic potential through inhibition of ERK/GSK3β/β-catenin signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 57:352-363. [PMID: 30831484 DOI: 10.1016/j.phymed.2018.12.033] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Revised: 12/27/2018] [Accepted: 12/29/2018] [Indexed: 06/09/2023]
Abstract
BACKGROUND Nerigoside (NG), a cardenolide isolated from a commonfolk medicine, Nerium oleander Linn. (Apocynaceae), has not been explored for its biological effects. To date, cardenolides have received considerable attention in pharmacology studies due to their direct effects of apoptosis-induction or growth-inhibitory against tumor in vitro and in vivo. Whether and how NG exerts anticancer effects against colorectal cancer remains to be elucidated. PURPOSE The aim of this study was to investigate the anticancer effect of NG in human colorectal cancer cells. METHODS To test anticancer effect, we compared potency of NG in two colorectal cancer cell lines, HT29 and SW620 by WST-1 and colony proliferation assays. And we investigated mechanism of anticancer activities by analyzing players in apoptotic and ERK/GSK3β/β-catenin signaling pathways in HT29 and SW620 cells treated with NG. RESULTS In this study, we showed that NG markedly suppressed the cell viability and colony formation of colorectal cancer cells HT29 and SW620, with no significant toxic effect on non-cancer cells NCM460. Annexin V-FITC/PI and CFSE labeling results revealed that NG suppressed cell proliferation in low concentration, along with reducing expression of PCNA, while NG induced apoptosis in high concentration,. Meanwhile, NG significantly arrested cell migration by reversal of EMT and cell cycle on G2/M. Then, we found that the ERK and GSK3β/β-catenin signaling pathway were noticeably blocked in CRC cells after treatment with NG. According to western blot, NG upregulated the expression of p-GSK3β/GSK3β and decreased especially the expression of β-catenin in nuclear. In addition, Wnt signaling and its target genes were suppressed in response to NG. Then, the Ser9 phosphorylation of GSK3β can be reduced / raised by GÖ 6983 / LiCl, respectively. Thus, we further confirmed that the GSK3β/β-catenin axis is involved in NG-prevented cell proliferation. CONCLUSION NG inhibited the growth of colorectal cancer cells by suppressing ERK/GSK3β/β-catenin signaling pathway. And the GSK3β/β-catenin axis is involved in preventing cell proliferation and migration by NG-treatment. These results suggest that NG may be used to treat colorectal cancer, with better outcome by combining with GSK3β inhibitor to block Wnt pathway.
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Affiliation(s)
- Shi-Yuan Wen
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Yan-Yan Chen
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Chun-Miao Deng
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Cui-Qiong Zhang
- Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, China
| | - Miao-Miao Jiang
- Tianjin State Key Laboratory of Modern Chinese Medicine, Pharmacology of Traditional Chinese Medicine Formulae, Tianjin University of Traditional Chinese Medicine, Tianjin 300193, China.
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49
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Interactions between cancer stem cells, immune system and some environmental components: Friends or foes? Immunol Lett 2019; 208:19-29. [DOI: 10.1016/j.imlet.2019.03.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 03/02/2019] [Accepted: 03/08/2019] [Indexed: 12/17/2022]
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50
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Dihydrotanshinone-Induced NOX5 Activation Inhibits Breast Cancer Stem Cell through the ROS/Stat3 Signaling Pathway. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:9296439. [PMID: 31019654 PMCID: PMC6451810 DOI: 10.1155/2019/9296439] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 11/14/2018] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are known to mediate metastasis and recurrence and are therefore a promising therapeutic target. In this study, we found that dihydrotanshinone (DHTS) inhibits CSC formation. DHTS inhibited mammosphere formation in a dose-dependent manner and showed significant tumor growth inhibition in a xenograft model. This compound reduced the CD44high/CD24low- and aldehyde dehydrogenase- (ALDH-) expressing cell population and the self-renewal-related genes Nanog, SOX2, OCT4, C-Myc, and CD44. DHTS induced NOX5 activation by increasing calcium, and NOX5 activation induced reactive oxygen species (ROS) production. ROS production reduced the nuclear phosphorylation levels of Stat3 and secreted IL-6 levels in the mammospheres. DHTS deregulated the dynamic equilibrium from non-stem cancer cells to CSCs by dephosphorylating Stat3 and decreasing IL-6 secretion and inhibiting CSC formation. These novel findings showed that DHTS-induced ROS deregulated the Stat3/IL-6 pathway and induced CSC death. NOX5 activation by DHTS inhibits CSC formation through ROS/Stat3/IL-6 signaling, and DHTS may be a promising potential therapeutic agent against breast CSCs.
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